ArticlePDF AvailableLiterature Review

Durvalumab: an investigational anti-PD-L1 monoclonal antibody for the treatment of urothelial carcinoma

Authors:

Abstract and Figures

Izak Faiena,1,2 Amy L Cummings,3 Anna M Crosetti,3 Allan J Pantuck,1,2 Karim Chamie,1,2 Alexandra Drakaki1–3 1Department of Urology, 2Institute of Urologic Oncology, 3Department of Medicine, Division of Hematology and Oncology, David Geffen School of Medicine at University of California, Los Angeles, CA, USA Abstract: Our expanding knowledge of immunotherapy for solid tumors has led to an explosion of clinical trials aimed at urothelial carcinoma. The primary strategy is centered on unleashing the immune system by releasing the inhibitory signals propagated by programmed cell death-1 (PD-1) and its ligand programmed cell death ligand-1 (PD-L1). Many antibody constructs have been developed to block these interactions and are used in clinical trials. The Food and Drug Administration has already approved a number of checkpoint inhibitors such as anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibodies including ipilimumab; anti-PD-1 monoclonal antibodies including nivolumab and pembrolizumab; anti-PD-L1 antibodies including atezolizumab, avelumab, and durvalumab. One of the latest inhibitors is durvalumab, which is a high-affinity human immunoglobulin G1 kappa monoclonal antibody and blocks the interaction of PD-L1 with PD-1 and CD80. Currently, there are a number of ongoing trials in advanced urothelial carcinoma both using durvalumab monotherapy and in combination with other targeted therapies. In addition, durvalumab is being investigated in the non-muscle-invasive urothelial carcinoma, which is centered around intravenous formulations. These exciting developments have added a significant number of therapies in a previously limited treatment landscape. Keywords: durvalumab, checkpoint inhibitors, metastatic urothelial carcinoma
Content may be subject to copyright.
© 2018 Faiena et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php
and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you
hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission
for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).
Drug Design, Development and Therapy 2018:12 209–215
Drug Design, Development and erapy Dovepress
submit your manuscript | www.dovepress.com
Dovepress 209
REVIEW
open access to scientific and medical research
Open Access Full Text Article
http://dx.doi.org/10.2147/DDDT.S141491
Durvalumab: an investigational anti-PD-L1
monoclonal antibody for the treatment of
urothelial carcinoma
Izak Faiena1,2
Amy L Cummings3
Anna M Crosetti3
Allan J Pantuck1,2
Karim Chamie1,2
Alexandra Drakaki1–3
1Department of Urology, 2Institute
of Urologic Oncology, 3Department
of Medicine, Division of Hematology
and On col ogy, David Geffen School of
Medicine at University of California,
Los Angeles, CA, USA
Abstract: Our expanding knowledge of immunotherapy for solid tumors has led to an explosion
of clinical trials aimed at urothelial carcinoma. The primary strategy is centered on unleashing
the immune system by releasing the inhibitory signals propagated by programmed cell death-1
(PD-1) and its ligand programmed cell death ligand-1 (PD-L1). Many antibody constructs have
been developed to block these interactions and are used in clinical trials. The Food and Drug
Administration has already approved a number of checkpoint inhibitors such as anti-cytotoxic
T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibodies including ipilimumab;
anti-PD-1 monoclonal antibodies including nivolumab and pembrolizumab; anti-PD-L1
antibodies including atezolizumab, avelumab, and durvalumab. One of the latest inhibitors is
durvalumab, which is a high-affinity human immunoglobulin G1 kappa monoclonal antibody
and blocks the interaction of PD-L1 with PD-1 and CD80. Currently, there are a number of
ongoing trials in advanced urothelial carcinoma both using durvalumab monotherapy and in
combination with other targeted therapies. In addition, durvalumab is being investigated in the
non-muscle-invasive urothelial carcinoma, which is centered around intravenous formulations.
These exciting developments have added a significant number of therapies in a previously
limited treatment landscape.
Keywords: durvalumab, checkpoint inhibitors, metastatic urothelial carcinoma
Introduction
Bladder cancer is the fourth most common cancer, with an estimated 76,960 new
cases per year and an estimated 16,390 deaths.1 Systemic cisplatin-based combina-
tion chemotherapies were the standard of care for patients with metastatic urothelial
bladder cancer (mUC) for the past 30 years up until recently when newer approvals
occurred. First-line systemic regimens included methotrexate, vinblastine, doxorubicin,
cisplatin (MVAC), and gemcitabine/cisplatin.2 Although a majority of patients with
metastatic disease (40%–70%) experience an initial response to chemotherapy, all
will ultimately progress with a median survival of 14 months and an overall 5-year
survival rate of only 5%–20%. Poor response to chemotherapy is further compounded
by many barriers to administer chemotherapy in this population where many patients
already have coexisting comorbidities including renal insufficiency that may preclude
them from receiving cisplatin therapy and instead being treated with carboplatin,
which has lower response rates.3 However, the treatment arena in this first-line setting
is changing with the introduction of immunooncology agents.2 Furthermore, different
chemotherapy regimens such as taxanes and pemetrexed have been used as second- or
Correspondence: Alexandra Drakaki
David Geffen School of Medicine,
University of California, 300 Stein Plaza,
Suite 348, Los Angeles, CA 90095, USA
Tel +1 310 794 2858
Fax +1 310 794 3513
Email adrakaki@mednet.ucla.edu
Journal name: Drug Design, Development and Therapy
Article Designation: Review
Year: 2018
Volume: 12
Running head verso: Faiena et al
Running head recto: Review of durvalumab
DOI: http://dx.doi.org/10.2147/DDDT.S141491
Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 196.53.21.69 on 24-Jan-2018
For personal use only.
Powered by TCPDF (www.tcpdf.org) 1 / 1
This article was published in the following Dove Press journal:
Drug Design, Development and Therapy
Drug Design, Development and Therapy 2018:12
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
210
Faiena et al
third-line treatments but again with decreased response rates
signifying a need for more therapeutic options that are now
finally becoming available.4
With the excitement over immunotherapy and its poten-
tial impact on cancer treatment, programmed cell death-1
(PD-1) receptor and its ligands, programmed cell death-1
ligand (PD-L1) and programmed cell death-2 ligand (PD-L2)
inhibitors have emerged as important additions to the treat-
ment of mUC. Over the past year, there have been five Food
and Drug Administration (FDA)-approved single agents that
have changed the treatment landscape in urothelial cancer –
in both the first- and second-line setting. PD-L1 and PD-L2
are vital receptor ligands in T-cell immunomodulation and
tolerance and have provided us with a critical target for
cancer therapy. The PD-1 receptor is expressed on activated
T cells, and PD-1–ligand interaction results in the inhibition
of T-cell receptor (TCR)-mediated functions and the suppres-
sion of T-cell effector function. Furthermore, PD-1 activity
is thought to act primarily in the tumor microenvironment,
where it restrains T-cell-mediated tumor destruction.5 The
upregulation of PD-L1 on tumor cells led to the activation
of the PD-1 pathway as a mechanism of immune evasion.6
Immunohistochemical studies have demonstrated that an
increased PD-L1 expression is associated with increasing
bladder tumor stage and grade.7
Immunotherapies as a novel concept
in cancer
Enlisting the power of the immune system to counter malig-
nancy is not unique to the 21st century. Spontaneous regres-
sion of tumors following erysipelas has been documented
since the 17th century. Surgeon William Coley8 injected mix-
tures of attenuated bacteria into inoperable tumors leading
to decreased tumor size in 190 of 312 cases in the 1890s.
In the 1970s, intravesicar Bacillus Calmette–Guérin (BCG)
vaccine, perhaps with some degree of serendipity, harnessed
the antigenicity and immunogenicity of bladder cancer to
achieve early-disease remission and prolong survival via an
immunomediated antitumor response.9
Mechanism of action
Over the past 30 years, this immunomediated antitumor
response has been drilled down to a T-cell-specific response,
which dovetailed with the development of monoclonal
antibodies,10 ushering in a new era of unbridled optimism
in immunotherapy targeted to the immune checkpoint. The
physiologic foundation of this response was well described
by Chen and Mellman11 in 2013 as a cancer-immunity
cycle initiated by the release of cancer cell antigens. In this
model, cancer antigens are taken up by antigen-presenting
cells (APCs), which prime and activate cytotoxic T cells
that in turn travel to and infiltrate tumor. In the tumor
microenvironment, primed TCRs recognize abnormal
proteins expressed through major histocompatibility
complex-I (MHC-I) of cancer cells, triggering granzyme
and perforin release, leading to rupture of tumor cell
membrane and destruction of the abnormal cell, starting
the cycle over again.11 Obviously, as cancer is able to
take hold in hosts with functioning immune systems, it is
a fallible system, but it was not until the theory of cancer
immunoediting that a model described how tumors have
been able to evade immune destruction. Dunn et al12 sug-
gested a model in 2002 that described this process as one
in which the immune system initially eliminates abnormal
cancer cells, but it reaches a point of equilibrium in which
tumor cell variants with increasing capacity to evade the
immune system are selected, thus facilitating tumor escape
from immunomediated destruction. Further research has
described how immune-impenetrable phenotypes and robust
tumor microenvironments13 as well as mutations disrupting
MHC–T-cell interaction14 and interferon-gamma signaling15
may contribute to tumor escape.
One of the proposed mechanisms of tumor escape is via
the immune checkpoint, an umbrella term for the complex
network of ligand–receptor co-signaling interactions on
the T-cell surface.16 There are two main types of T-cell
regulatory ligand–receptors: the immunoglobulin (Ig)
or B7 superfamily and the tumor necrosis factor (TNF)
family.17 The Ig family includes co-inhibitory receptors
such as cytotoxic T-lymphocyte-associated protein 4
(CTLA4) and PD-1, which interact with APC CD80 or
CD86 or PD-L1, respectively.18 When these co-inhibitory
receptors are engaged, T-cell activation is blocked via
recruitment of Src homology 2 domain-containing protein
tyrosine family phosphatases (SHPs), which reverse TCR
activation-induced phosphorylation of signaling molecules,
preventing the release of granyzmes and perforins even if
a TCR has recognized abnormal protein on the MHC-I.19
Co-stimulatory receptors, such as OX40, belong to the
TNF family and, when activated, recruit TNF receptor
(TNFR)-associated factors (TRAFs) that differentially
activate mitogen-activated protein kinase (MAPK) signal-
ing cascades, promoting nuclear factor-κB that enhances
cellular proliferation and function (Figure 1).17 Both
mechanisms have been exploited, in vivo and in vitro, by
monoclonal antibodies.
Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 196.53.21.69 on 24-Jan-2018
For personal use only.
Powered by TCPDF (www.tcpdf.org) 1 / 1
Drug Design, Development and Therapy 2018:12 submit your manuscript | www.dovepress.com
Dovepress
Dovepress
211
Review of durvalumab
Antibodies that have been designed to block negative
co-stimulatory molecules or activate co-stimulatory mol-
ecules have been in development over the past decade.
Current FDA-approved treatments include anti-CTLA4
monoclonal antibodies including ipilimumab; anti-PD-1
monoclonal antibodies including nivolumab and pembroli-
zumab; and anti-PD-L1 antibodies including atezolizumab,
avelumab, and durvalumab. Ideally, by blocking receptors
or ligands that dampen immune activity, these agents rein-
vigorate or expand T-cell anticancer response11 and may act
by opsonizing tumor cells and triggering death or removal
by antibody-dependent cellular cytotoxicity or phagocyto-
sis.16 Durvalumab is a human immunoglobulin G1 kappa
monoclonal antibody that blocks the interaction of PD-L1
with PD-1 and CD80 and works through this mechanism
(Figure 2).
Patient selection
PD-1/L1 expression in both tumor and immune cells are
often used as markers for response to inhibit T-cell function.
Intuitively, patients who overexpress PD-1/L1 are more
likely to show a favorable response when inhibited by the
antibodies, which would release the breaks on the immune
system. However, the expected response in these patients is
underwhelming. Some theories suggest that there may be
an unmeasured interplay between the ligand and the recep-
tor, or the tumor heterogeneity.20 Therefore, in practice,
currently, patients are not selected based on the expression
status. However, trials often sub-stratify patients based on the
expression profile, which may inform further understanding
of the tumor–immune milieu.
Metastatic urothelial carcinoma
Current therapies
The list of PD-1/L1 inhibitors continues to grow (Table 1).
The efficacy of the agents in recent trials has led to the
FDA approval for use in metastatic urothelial carcinoma.
Atezolizumab, a PD-L1 inhibitor, was recently approved
based on the Phase II IMvigor 210 (NCT02108652) trial.21
The trial consisted of patients with locally advanced or
metastatic urothelial carcinoma who were cisplatin ineligible
(n=119) or who progressed after receiving platinum-based
chemotherapy (n=310). The overall response rate (ORR)
for the cohort in the second-line setting was 15% (95% CI,
11%–20%; p=0.006) and conferred a median overall survival
(OS) of 7.9 months and a 12-month OS of 36%. In patients
who had tumor samples tested for PD expression, the ORR
for IC2/3 was 27% (95% CI, 19%–37%; p,0.0001) and for
IC1/2/3 was 18% (95% CI, 13%–24%; p=0.0004). The safety
and efficacy of avelumab (PD-L1 inhibitor) were investigated
in JAVELIN (NCT01772004), a Phase Ib trial in the second-
line setting (n=44).22 The ORR was 18.2%, five of whom
had complete responses and three with partial responses.
The median OS was 13.7 months. When stratifying by a
7XPRUFHOO
2;/
%
0+&,
%
3'/
3'
&7/$
7&5
&'
2;
3,.$.7 6+3
6LJQDO 7FHOO
±
75$)V
Figure 1 Immune checkpoint paths and interactions.
Notes: Major inhibitory and stimulatory pathways through the TCR. CTLA4, PD-1
and PD-L1, OX40 (tumor necrosis factor receptor superfamily, member 4), and
OX40L, PI3K-AKT, SHP2, and TRAF pathways.
Abbreviations: TCR, T-cell receptor; CTLA4, Cytotoxic T-lymphocyte-associated
protein 4; PD-1, programmed cell death-1; PD-L1, programmed cell death ligand-1;
OX40L, OX40 ligand; PI3K-AKT, phosphoinositide 3-kinase-protein kinase B; SHP2,
Src homology 2 domain-containing protein tyrosine phosphatase; TRAFs, tumor
necrosis factor receptor-associated factors.
3HUIRULQVDQG
JUDQ]\PHV
0+&, 7&5
$FWLYDWHG
7FHOO
6WLPXODWLRQ
2II
6+3
3'3'/
7XPRU
FHOO
'XUYDOXPDE
1HRHSLWRSH
&RLQKLELWRU\
VLJQDOLQJ
Figure 2 Mechanism of durvalumab.
Notes: Durvalumab antibody blocks PD-1 and PD-L1 interaction, which prevents
a SHP2-mediated co-inhibitory signal, allowing the neoepitope expressed by MHC-I
to act as signal in stimulating an immune response, leading to the release of perforins
and granzymes, theoretically leading to destruction of the tumor cell.
Abbreviations: PD-1, programmed cell death-1; PD-L1, programmed cell death
ligand-1; SHP2, Src homology 2 domain-containing protein tyrosine phosphatase;
MHC, major histo compatibility complex; TCR, T-cell receptor.
Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 196.53.21.69 on 24-Jan-2018
For personal use only.
Powered by TCPDF (www.tcpdf.org) 1 / 1
Drug Design, Development and Therapy 2018:12
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
212
Faiena et al
PD-L1 expression cutoff of 5%, patients with positive and
negative expressions had an ORR of 53.8% (7/13) and 4.2%
(1/24), respectively. Pembrolizumab, a PD-1 inhibitor, was
evaluated in KEYNOTE-045 (NCT02256436), which was
a Phase III, open-label, 1:1 randomized trial of pembroli-
zumab versus investigator’s choice of docetaxel, paclitaxel,
or vinflunine in patients who progressed on platinum-based
chemotherapy.23 The median OS was 10.3 months (95%
CI, 8.0–11.8) in the pembrolizumab group, compared with
7.4 months (95% CI, 6.1–8.3) in the chemotherapy group
(hazard ratio [HR], 0.73; 95% CI, 0.59–0.91; p=0.002), and
this difference remains at the 2-year landmark. Furthermore,
the median OS in patients who had a tumor PD-L1 expres-
sion score of $10% was 8.0 months (95% CI, 5.0–12.3)
in the pembrolizumab group, compared with 5.2 months
(95% CI, 4.0–7.4) in the chemotherapy group (HR, 0.57;
95% CI, 0.37–0.88; p=0.005). Another PD-1 inhibitor, niv-
olumab, was evaluated in a Phase II trial (CheckMate 275;
NCT02387996) looking at the primary endpoint of ORR in
the second-line setting.24 There were 52 of 265 responders
who achieved an ORR of 19.6% (95% CI, 15.0–24.9) with
a median OS of 8.7 months. The ORR for patients with PD
expression $5% was 23.8% (95% CI, 16.5–32.3) compared
with only 16.1% (95% CI, 10.5–23.1) in patients with PD
expression $1%.
Durvalumab
Durvalumab is an IgG1 monoclonal antibody that has high-
affinity binding to PD-L1 receptor. Currently, it is being
evaluated for treatment in multiple malignancies in an ongo-
ing Phase I/II trial (NCT01693562). This study is evaluating
the safety and efficacy of durvalumab in patients with urothe-
lial carcinoma among other histologies who progressed on
chemotherapy and have never received any immunotherapy
or refused other treatments. The main dose was 10 mg/kg
every 2 weeks, for up to 12 months or up to progression,
initiation of a different therapy, experience of intolerable side
effects, or withdrawal. The primary endpoint is safety and
secondary endpoint consisted of efficacy outcomes (ORR,
disease control at 12 weeks, and PD expression status).
The initial report was on 61 patients, 20 of whom initially
enrolled regardless of PD-L1 expression status; however,
subsequent patients were required to have .5% expression
in the tumor cells for enrollment.25 Furthermore, given earlier
data from small-cell lung cancer, they used a cutoff of $25%
of tumor or immune cells expressing PD-L1 as positive as
these patients were enriched for response. In this cohort,
64% of patients had an adverse event (AE). The most com-
mon adverse events were fatigue, diarrhea, and decreased
appetite. Grade 3 AE were reported in 4.9% of the patients
with no grade 4 or 5 AE. The ORR was 31.0% (95% CI,
17.6%–47.1%) with 46.4% in the PD-L1-positive subgroup
(.25% expression) and 0% in the PD-L1-negative subgroup
(,25% expression). The disease control rate at 12 months
for the same subgroups was 57.1% and 28.6%, respectively.
Responders in the PD-L1-positive subgroup had a median
time to response of 6.3 weeks (95% CI, 5.6–12.1 weeks).
Overall, this study demonstrated an effective and durable
response rate with an acceptable safety profile.
In an update of the expansion cohort from the same
trial (NCT01693562), 191 patients were enrolled with a
significant proportion with relatively poor prognosis, 97%
of whom had previous platinum-based therapy. In addition,
95% had visceral metastases and 49% had liver metastases.26
In the cohort, the ORR was 17.8% (95% CI, 12.7%–24.0%),
which included seven patients with a complete response.
The ORRs in PD-L1-positive patients was 27.6% (95% CI,
19.0%–37.5%) compared with 5.1% (95% CI, 1.4%–12.5%)
in PD-L1-negative patients. The response rate in other sub-
groups was also significant. In patients with lymph node
metastases, the ORR was 50.0% (95% CI, 23.0%–77.0%).
In patients with visceral metastases or liver metastases, the
ORR was 15.3% (95% CI, 10.3%–21.4%) and 7.3% (95%
CI, 2.7%–15.2%), respectively. With limited follow-up, the
progression-free survival (PFS) was 2.1 months (95% CI,
1.4–2.8) in the PD-L1-positive group and 1.4 months in
the PD-L1-negative group (95% CI, 1.3–1.5). In addition,
the data for OS were immature, but the authors report a
median OS of 18.2 months in the treated group. The safety
profile report consisted of common AEs, which were fatigue
Table 1 Approved drugs for locally advanced or metastatic urothelial carcinoma
Drug Target Trial Indication Phase ORR (%) Median OS
(months)
PFS
(months)
Atezolizumab PD-L1 NCT02108652 Cis-ineligible or progression on platinum II 15 7.9 2.1
Avelumab PD-L1 NCT01772004 Progression on platinum Ib 18.2 13.7 11.6 (w)
Pembrolizumab PD-1 NCT02256436 Progression on platinum III 21.1 10.3 2.1
Nivolumab PD-1 NCT02387996 Progression on platinum II 19.6 8.7 NR
Durvalumab PD-L1 NCT01693562 Progression on platinum I/II 17.8 18.2 2.1
Abbreviations: ORR, overall response rate; OS, overall survival; PD-L1, programmed cell death ligand-1; PFS, progression-free survival; NR, non reported; w, weeks.
Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 196.53.21.69 on 24-Jan-2018
For personal use only.
Powered by TCPDF (www.tcpdf.org) 1 / 1
Drug Design, Development and Therapy 2018:12 submit your manuscript | www.dovepress.com
Dovepress
Dovepress
213
Review of durvalumab
(19.4%), decreased appetite (9.4%), diarrhea (8.4%), and rash
(7.3%). Overall, grade 3 or 4 treatment-related AEs occurred
in 6.8% of the trial cohort.
Currently, the Phase III trial DANUBE (NCT02516241)
is evaluating durvalumab in the first-line setting in patients
with locally advanced or metastatic urothelial carcinoma.
In this trial, patients are randomized to durvalumab mono-
therapy, durvalumab combination therapy with tremelimumab
(anti-CTLA-4 antibody), or standard of care chemotherapy
(either cisplatin–gemcitabine or carboplatin–gemcitabine).
Patients are further stratified by eligibility to receive chemo-
therapy based on the PD-L1 expression and the presence or
absence of visceral metastases. The primary endpoints are
PFS and OS. To date, the results are pending.
Despite the success of monotherapy, there are still
patients who progress or do not respond to initial treatment,
which sparked an interest in combination therapy. Ongo-
ing trials include BISCAY (NCT02546661), which is a
Phase Ib trial recruiting patients with metastatic UC who
are randomized to durvalumab in combination with multiple
agents (durvalumab monotherapy, durvalumab + AZD4547
[fibroblast growth factor receptor tyrosine kinase family
inhibitor], durvalumab + olaparib [poly(ADP-ribose) poly-
merase inhibitor], durvalumab + AZD1775 [Wee1 kinase
inhibitor], and durvalumab + vistusertib [mammalian target
of rapamycin]) with primary safety endpoint. This trial will
be offered to patients who are immunotherapy naive. In the
Phase II BASKET study (NCT02527434), patients with
metastatic urothelial cancer with or without prior treatment
with PD1 or PD-L1 inhibitors were recruited to receive the
combination of tremelimumab with durvalumab. The primary
endpoint is objective response rate, and the results of this
study are still pending. Finally, a combination of durvalumab
and tremelimumab with or without a toll-like receptor 3
agonist (PolyICLC) is being evaluated in a Phase I/II trial
(NCT02643303) with the primary endpoint being safety and
tolerability as well as ORR, PFS, and OS.
Non-muscle-invasive bladder cancer
(NMIBC)
Current therapies
Treatments for NMIBC represent the earliest forms of immu-
notherapy for bladder cancer. The introduction of BCG to
the armamentarium by the urologist was revolutionary as
it provided a local treatment with manageable side effects
with durable efficacy and is currently the preferred adju-
vant treatment for high-risk NMIBC.27 Although the exact
underlying mechanisms of the efficacy of intravesical BCG
are incompletely elucidated, it is generally accepted that
immune response to BCG plays a part28 in conjunction with
both urothelial cells and bladder cancer cells.29 However,
there is a high failure rate associated with BCG treatment
that includes recurrence and more worrisome, progression.
Furthermore, production shortages for BCG have placed
constraints on treatment of NMIBC. As such, there is an
increased pressure for other treatment strategies with similar
efficacy. Current treatments center upon chemotherapeutic
agents delivered intravesically in the second-line setting such
as mitomycin C, thiotepa, gemcitabine, docetaxel, valrubicin,
and epirubicin with different combinations thereof with or
without immune modulators (eg, interleukin-15).
There has been great interest in potentiating the immune
system as it has clearly worked using BCG. The excitement
with the efficacy of checkpoint inhibitors in the advanced
UC setting has spilled over to the NMIBC setting. This is
reasonable as PD-L1 expression in tumor cells has been
associated with prior BCG treatment, perhaps pointing to
a potential resistance mechanism.30 Currently, there are a
number of trials incorporating checkpoint inhibitors in the
second-line setting. For example, an ongoing Phase II trial
(NCT02844816) is evaluating the complete response rate
in BCG-unresponsive patients using IV atezolizumab every
21 days for up to 17 courses (51 weeks) in the absence
of disease progression or unacceptable toxicity. Another
Phase II trial (NCT02625961) is evaluating pembrolizumab
(IV 200 mg Q3 weeks) in BCG-unresponsive patients.
Treatment duration is 24 months or until disease recurrence
or progression, unacceptable toxicity, withdrawal, or inves-
tigator decision. The patients are further stratified by the
presence or absence of CIS based on tissue pathology at
screening. Follow-up plan is cystoscopy and urine cytology
every 12 weeks for the first 2 years, every 24 weeks for the
following 2 years, and every 52 weeks thereafter. Co-primary
endpoints are complete response rate and disease-free sur-
vival. Other strategies are to combine checkpoint inhibitors
with BCG. A Phase Ib/II trial (NCT02792192) is assess-
ing the safety and tolerability of IV atezolizumab infusion
alone and in combination with intravesical BCG in high-risk
NMIBC patients. Other strategies include using intravesical
checkpoint inhibitors, as a current Phase I dose escalation
trial (NCT02808143) aims to assess the safety of combina-
tion intravesical BCG and pembrolizumab in patients with
refractory NMIBC.
Durvalumab in NMIBC
Given the evidence that durvalumab is effective in advanced
setting, currently, it is being studied in patients with non-
muscle-invasive disease. A Phase II trial (NCT02901548)
Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 196.53.21.69 on 24-Jan-2018
For personal use only.
Powered by TCPDF (www.tcpdf.org) 1 / 1
Drug Design, Development and Therapy 2018:12
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
214
Faiena et al
is under way to assess the combination of IV durvalumab
and BCG in patients with BCG-refractory disease. The main
inclusion criteria are high-grade carcinoma in situ (CIS) at
6 months after BCG treatment, progression at 3 months after
induction BCG, recurrence of high-grade CIS, or persistent
CIS noted in the bladder biopsies within 3 months of complet-
ing at least two induction treatments with BCG. Patients will
be assigned to a single arm of IV durvalumab 1,500 mg/kg Q4
weeks for a total of 12 months. Posttreatment assessment will
include cystoscopy with biopsy and transurethral resection of
the bladder tumor (TURBT) at baseline, 3, 6, 9, 12, 18, and
24 months after the first treatment. Mapping biopsies will
be conducted at 6 and 24 months. The primary outcome is
complete response rate at 6 months, whereas the secondary
endpoint is complete response rate at 24 months.
Conclusion
In the past decade, the use of monoclonal antibodies to
unshackle T-cells from their checkpoint inhibition has
revolutionized immunotherapy, but the treatment remains
fettered by unreliable responses, late relapses, unpredictable
autoimmune phenomena, and complex microenvironment
interactions limiting our ability to select likely responders.
Both innate and adaptive checkpoint inhibitor resistances
have been described,13 and the field is rapidly accumulating
whole-exome sequencing data correlated with clinical
information to tease apart the nuances of the complicated
interaction between the immune system and the cancer
growth. Human leukocyte antigen heterogeneity, mutational
load, TCR clonality, and T-cell tumor penetration are all
active areas of interest.
While we are awaiting the results of further translational
research, clinical data continue to amass. Investigators of
checkpoint inhibitor clinical trials have strategized to manip-
ulate subpar ORR by bringing the agents front line21,31 or as
neoadjuvant32,33 treatment, more carefully selecting patients
through biomarkers34–36 and combining immunotherapies37–40
or combining approaches. These strategies have been met
with variable success. More recently, attention has been
directed toward combining checkpoint inhibitors with
other treatments with nonoverlapping toxicities, such as
chemotherapy36,41,42 or other inhibitors of tumor-mediated
immune suppression outside the immune checkpoint
pathways.43 While somewhat controversial, this approach
stands on the foundation of work by Galluzzi et al44,45 who
revealed that certain types of chemotherapy and radiation
may heighten antigenicity and adjuvanticity and improve
response to checkpoint inhibition.
As our treatment armamentarium for urothelial carci-
noma continues to expand, checkpoint inhibitors appear at
the center of the current treatment paradigm. Many trials are
currently ongoing to refine our treatment strategies while
exploring more novel ways to approach treatment in hopes
of providing hope for an otherwise lethal disease.
Disclosure
The authors report no conflicts of interest in this work.
References
1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J
Clin. 2016;66(1):7–30.
2. Sternberg CN, de Mulder P, Schornagel JH, et al. Seven year update of
an EORTC phase III trial of high-dose intensity M-VAC chemotherapy
and G-CSF versus classic M-VAC in advanced urothelial tract tumours.
Eur J Cancer. 2006;42(1):50–54.
3. Bellmunt J, Petrylak DP. New therapeutic challenges in advanced
bladder cancer. Semin Oncol. 2012;39(5):598–607.
4. Sweeney CJ, Roth BJ, Kabbinavar FF, et al. Phase II study of pemetr-
exed for second-line treatment of transitional cell cancer of the urothe-
lium. J Clin Oncol. 2006;24(21):3451–3457.
5. Donin NM, Lenis AT, Holden S, et al. Immunotherapy in the treatment
of urothelial carcinoma. J Urol. 2017;197(1):14–22.
6. Dong H, Strome SE, Salomao DR, et al. Tumor-associated B7-H1
promotes T-cell apoptosis: a potential mechanism of immune evasion.
Nat Med. 2002;8(8):793–800.
7. Huang Y, Zhang SD, McCrudden C, Chan KW, Lin Y, Kwok HF.
The prognostic significance of PD-L1 in bladder cancer. Oncol Rep.
2015;33(6):3075–3084.
8. Nauts HC, Swift WE, Coley BL. The treatment of malignant tumors
by bacterial toxins as developed by the late William B Coley, M.D.,
reviewed in the light of modern research. Cancer Res. 1946;6:
205–216.
9. Morales A, Eidinger D, Bruce AW. Intracavitary Bacillus Calmette-
Guerin in the treatment of superficial bladder tumors. J Urol. 1976;
116(2):180–183.
10. Kohler G, Milstein C. Continuous cultures of fused cells secreting
antibody of predefined specificity. Nature. 1975;256(5517):495–497.
11. Chen DS, Mellman I. Oncology meets immunology: the cancer-
immunity cycle. Immunity. 2013;39(1):1–10.
12. Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD. Cancer immu-
noediting: from immunosurveillance to tumor escape. Nat Immunol.
2002;3(11):991–998.
13. Hugo W, Zaretsky JM, Sun L, et al. Genomic and transcriptomic fea-
tures of response to anti-PD-1 therapy in metastatic melanoma. Cell.
2016;165(1):35–44.
14. del Campo AB, Kyte JA, Carretero J, et al. Immune escape of cancer
cells with beta2-microglobulin loss over the course of metastatic mela-
noma. Int J Cancer. 2014;134(1):102–113.
15. Garcia-Diaz A, Shin DS, Moreno BH, et al. Interferon receptor sig-
naling pathways regulating PD-L1 and PD-L2 expression. Cell Rep.
2017;19(6):1189–1201.
16. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of
age. Nature. 2011;480(7378):480–489.
17. Yao S, Zhu Y, Chen L. Advances in targeting cell surface signalling
molecules for immune modulation. Nat Rev Drug Discov. 2013;12(2):
130–146.
18. Pardoll DM. The blockade of immune checkpoints in cancer immuno-
therapy. Nat Rev Cancer. 2012;12(4):252–264.
19. Ribas A. Releasing the brakes on cancer immunotherapy. N Engl J
Med. 2015;373(16):1490–1492.
Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 196.53.21.69 on 24-Jan-2018
For personal use only.
Powered by TCPDF (www.tcpdf.org) 1 / 1
Drug Design, Development and erapy
Publish your work in this journal
Submit your manuscript here: http://www.dovepress.com/drug-design-development-and-therapy-journal
Drug Design, Development and Therapy is an international, peer-
reviewed open-access journal that spans the spectrum of drug design
and development through to clinical applications. Clinical outcomes,
patient safety, and programs for the development and effective, safe,
and sustained use of medicines are the features of the journal, which
has also been accepted for indexing on PubMed Central. The manu-
script management system is completely online and includes a very
quick and fair peer-review system, which is all easy to use. Visit
http://www.dovepress.com/testimonials.php to read real quotes from
published authors.
Drug Design, Development and Therapy 2018:12 submit your manuscript | www.dovepress.com
Dovepress
Dovepress
Dovepress
215
Review of durvalumab
20. Drake CG, Bivalacqua TJ, Hahn NM. Programmed cell death ligand-1
blockade in urothelial bladder cancer: to select or not to select. J Clin
Oncol. 2016;34(26):3115–3116.
21. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in
patients with locally advanced and metastatic urothelial carcinoma who
have progressed following treatment with platinum-based chemother-
apy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):
1909–1920.
22. Apolo AB, Infante JR, Balmanoukian A, et al. Avelumab, an anti-
programmed death-ligand 1 antibody, In patients with refractory
metastatic urothelial carcinoma: results from a multicenter, phase Ib
study. J Clin Oncol. 2017;35(19):2117–2124.
23. Bellmunt J, de Wit R, Vaughn DJ, et al. Pembrolizumab as second-
line therapy for advanced urothelial carcinoma. N Engl J Med. 2017;
376(11):1015–1026.
24. Sharma P, Retz M, Siefker-Radtke A, et al. Nivolumab in metastatic
urothelial carcinoma after platinum therapy (CheckMate 275): a multi-
centre, single-arm, phase 2 trial. Lancet Oncol. 2017;18(3):312–322.
25. Massard C, Gordon MS, Sharma S, et al. Safety and efficacy of dur-
valumab (MEDI4736), an anti-programmed cell death ligand-1 immune
checkpoint inhibitor, in patients with advanced urothelial bladder
cancer. J Clin Oncol. 2016;34(26):3119–3125.
26. Powles T, O’Donnell PH, Massard C, et al. Efficacy and safety of
durvalumab in locally advanced or metastatic urothelial carcinoma:
updated results from a phase 1/2 open-label study. JAMA Oncol. 2017;
3(9):e172411.
27. Sylvester RJ, van der MA, Lamm DL. Intravesical bacillus Calmette-
Guerin reduces the risk of progression in patients with superficial
bladder cancer: a meta-analysis of the published results of randomized
clinical trials. J Urol. 2002;168(5):1964–1970.
28. Patard JJ, Saint F, Velotti F, Abbou CC, Chopin DK. Immune response
following intravesical bacillus Calmette-Guerin instillations in super-
ficial bladder cancer: a review. Urol Res. 1998;26(3):155–159.
29. Redelman-Sidi G, Glickman MS, Bochner BH. The mechanism of
action of BCG therapy for bladder cancer – a current perspective. Nat
Rev Urol. 2014;11(3):153–162.
30. Inman BA, Sebo TJ, Frigola X, et al. PD-L1 (B7-H1) expression by
urothelial carcinoma of the bladder and BCG-induced granulomata:
associations with localized stage progression. Cancer. 2007;109(8):
1499–1505.
31. Balar AV, Galsky MD, Rosenberg JE, et al. Atezolizumab as first-line
treatment in cisplatin-ineligible patients with locally advanced and
metastatic urothelial carcinoma: a single-arm, multicentre, phase 2
trial. Lancet. 2017;389(10064):67–76.
32. Chaft JE, Forde PM, Smith KN, et al. Neoadjuvant nivolumab in
early-stage, resectable non-small cell lung cancers [abstract]. American
Society of Clinical Oncology (ASCO) Annual Meeting. Chicago, IL;
2017. Abstract number 8505.
33. Uppaluri R, Zolkind P, Lin T, et al. Neoadjuvant pembrolizumab in
surgically resectable, locally advanced HPV negative head and neck
squamous cell carcinoma (HNSCC) [abstract]. American Society of
Clinical Oncology Annual Meeting (ASCO) Annual Meeting. Chicago,
IL; 2017. Abstract number 6012.
34. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of
non-small-cell lung cancer. N Engl J Med. 2015;372(21):2018–2028.
35. Reck M, Rodriguez-Abreu D, Robinson AG, et al. Pembrolizumab
versus chemotherapy for PD-L1-positive non-small-cell lung cancer.
N Engl J Med. 2016;375(19):1823–1833.
36. Carbone DP, Reck M, Paz-Ares L, et al. First-line nivolumab in
stage IV or recurrent non-small-cell lung cancer. N Engl J Med.
2017;376(25):2415–2426.
37. Postow MA, Chesney J, Pavlick AC, et al. Nivolumab and ipilimumab
versus ipilimumab in untreated melanoma. N Engl J Med. 2015;
372(21):2006–2017.
38. Hodi FS, Chesney J, Pavlick AC, et al. Combined nivolumab and
ipilimumab versus ipilimumab alone in patients with advanced mela-
noma: 2-year overall survival outcomes in a multicentre, randomised,
controlled, phase 2 trial. Lancet Oncol. 2016;17(11):1558–1568.
39. Hellmann MD, Rizvi NA, Goldman JW, et al. Nivolumab plus ipili-
mumab as first-line treatment for advanced non-small-cell lung cancer
(CheckMate 012): results of an open-label, phase 1, multicohort study.
Lancet Oncol. 2017;18(1):31–41.
40. Antonia SJ, Gettinger SN, Goldman J, et al. ORAL01.03: CheckMate
012: safety and efficacy of first-line nivolumab and ipilimumab in
advanced NSCLC: topic: medical oncology. J Thorac Oncol. 2016;
11(11S):S250–S251.
41. Langer CJ, Gadgeel SM, Borghaei H, et al. Carboplatin and pemetrexed
with or without pembrolizumab for advanced, non-squamous non-
small-cell lung cancer: a randomised, phase 2 cohort of the open-label
KEYNOTE-021 study. Lancet Oncol. 2016;17(11):1497–1508.
42. Paz-Ares L, Brahmer J, Hellman MD, et al. CheckMate 227: a random-
ized, open-label phase 3 trial of nivolumab, nivolumab plus ipilimumab,
or nivolumab plus chemotherapy versus chemotherapy in advanced non-
small cell lung carcinoma [abstract]. European Lung Cancer Conference
(ELCC). Geneva, Switzerland; 2017. Abstract number 144TiP.
43. Hamid O, Bauer TM, Spira AI, et al. Safety of epacadostat 100 mg bid
plus pembrolizumab 200 mg Q3W in advanced solid tumors: phase 2
data from ECHO-202/KEYNOTE-037 [abstract]. American Society of
Clinical Oncology (ASCO) Annual Meeting. Chicago, IL; 2017. Abstract
number 3012.
44. Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G. Immunological
effects of conventional chemotherapy and targeted anticancer agents.
Cancer Cell. 2015;28(6):690–714.
45. Galluzzi L, Buque A, Kepp O, Zitvogel L, Kroemer G. Immunogenic
cell death in cancer and infectious disease. Nat Rev Immunol. 2017;
17(2):97–111.
Drug Design, Development and Therapy downloaded from https://www.dovepress.com/ by 196.53.21.69 on 24-Jan-2018
For personal use only.
Powered by TCPDF (www.tcpdf.org) 1 / 1
... Nivolumab, camrelizumab, tislelizumab, and toripalimab are all monoclonal IgG4 antibodies that bind PD-1 and prevents its interaction with PD-L1 [47][48][49][50]. Similarly, durvalumab is a monoclonal IgG1 antibody that binds PD-L1 and prevents its interaction with PD-1 [51]. As such, all the aforementioned agents halt the inactivation of immune cells by tumor cells, allowing for the restoration of an immune attack on malignant tissues. ...
Article
Full-text available
The emerging field of immuno-oncology has brought exciting developments in the treatment of hepatocellular carcinoma (HCC). It has also raised urgent questions about the role of immunotherapy in the setting of liver transplantation, both before and after transplant. A growing body of evidence points to the safety and efficacy of immunotherapeutic agents as potential adjuncts for successful down-staging of advanced HCCs to allow successful transplant in carefully selected patients. For patients with recurrent HCC post-transplant, immunotherapy has a limited, yet growing role. In this review, we describe optimal regimens in the setting of liver transplantation.
... In pretreated metastatic urothelial carcinoma, Atezolizumab showed a response of 40%, with a 3-year OS rate of 27% and a median overall survival of 14.6 months in patients with PD-L1 expression [28]. The effectiveness of Durvalumab was also analyzed and the subgroup with positive PD-L1 expression shows an ORR of 27.6%, with a median PFS of 2.1 months and an OS of 20 months [28], suggesting that it can be a therapeutic strategy as monotherapy and combined therapy [29]. ...
Article
Full-text available
Immune checkpoint inhibition (ICI) has emerged as a therapeutic option for acute myeloid leukemia (AML) for patients that suffer from relapsed or high-risk disease, or patients ineligible for standard therapy. We aimed to study ICI as monotherapy and/or combined therapy (with chemotherapy (QT), for AML patients. The PRISMA statement was used. The literature used comprised clinical trials, randomized controlled trials, and systematic reviews published within the last 7 years. The blockade of CTLA-4 presented a 42% of complete remission within AML. Nivolumab in high-risk AML showed a median recurrence-free survival (RFS) of 8.48 months. The same drug on relapsed hematologic malignancies after allogenic transplantation shows a 1-year OS of 56%. The use of prophylaxis post allogenic transplantation cyclophosphamide (PTCy), following checkpoint inhibition, demonstrated different baseline disease and transplantation characteristics when compared to no-PCTy patients, being 32% and 10%, respectively. CTLA-4 blockage was a worthy therapeutic approach in relapsed hematologic malignancies, presenting long-lasting responses. The approach to AML and myelodysplastic syndrome patients with ICI before allogenic hematopoietic stem cell transplantation and the use of a graft-versus-host disease prophylaxis have shown improvement in the transplantation outcomes, and therefore AML treatment.
... The indications were then expanded to include refractory NSCLC and SCLC. Some common side effects are associated with durvalumab including fatigue, headache, pain, diarrhea, weight loss, and so forth (54). ...
Article
Full-text available
Lung cancer is one of the deadliest types of cancer responsible for thousands of cancer-related deaths. Its treatment has remained a challenge for researchers, but an increase in the knowledge of molecular pathways and biology of lung cancer has dramatically changed its management in recent decades. Immunotherapies and immunomodulation of lung cancer have previously failed for a long time but thanks to continuous research work and enthusiasm, now, this field is emerging as a novel effective therapy. Now, it is hope with potential benefits and promising results in the treatment of lung cancer. This review article focuses on immune checkpoints inhibitors: CTLA-4 inhibitors (ipilimumab and tremelimumab) and PDL-1 inhibitors (durvalumab and atezolizumab) that can be blocked to treat lung carcinoma. It is also focused on critically analyzing different studies and clinical trials to determine the potential benefits, risks, and adverse events associated with immunotherapeutic treatment.
... Nivolumab is already approved for unresectable or metastatic melanoma, metastatic non-small cell lung carcinoma (NSCLC) after platinum-based chemotherapy, and metastatic renal cell carcinoma in the second-line setting [76]. Durvalumab has been approved to treat adult patients with unresectable stage III NSCLC and as a first-line treatment for adult patients with extensive-stage small-cell lung cancer (ES-SCLC) [77]. Cemiplimab is allowed as a first-line treatment in patients with NSCLC with >50% PD-L1 expression and cutaneous squamous cell carcinoma (CSCC) that is metastatic or locally advanced and not amenable to surgery. ...
Article
Full-text available
Glioblastoma multiforme (GBM) is the deadliest and the most heterogeneous brain cancer. The median survival time of GBM patients is approximately 8 to 15 months after initial diagnosis. GBM development is determined by numerous signaling pathways and is considered one of the most challenging and complicated-to-treat cancer types. Standard GBM therapy consist of surgery followed by radiotherapy or chemotherapy, and combined treatment. Current standard of care (SOC) does not offer a significant chance for GBM patients to combat cancer, and the selection of available drugs is limited. For almost 20 years, there has been only one drug, Temozolomide (TMZ), approved as a first-line GBM treatment. Due to the limited efficacy of TMZ and the high rate of resistant patients, the implementation of new chemotherapeutics is highly desired. However, due to the unique properties of GBM, many challenges still need to be overcome before reaching a ‘breakthrough’. This review article describes the most recent compounds introduced into clinical trials as drug candidates for GBM chemotherapy.
... As model targets, the extracellular domains of PD-L1 (PD-L1-ECD) and EGFR (EGFR-ECD) were chosen. Currently, various monoclonal antibodies targeting either EGFR, including the therapeutic antibodies panitumumab (37), necitumumab (38), nimotuzumab (39) and cetuximab (40), or PD-L1, among them durvalumab (41), avelumab (42) and atezolizumab (43) are approved for tumor treatment in multiple countries. Recently, our group isolated a chicken-derived anti-PD-L1 antibody called ICI2 (44). ...
Article
Full-text available
Various formats of bispecific antibodies exist, among them Two-in-One antibodies in which each Fab arm can bind to two different antigens. Their IgG-like architecture accounts for low immunogenicity and also circumvents laborious engineering and purification steps to facilitate correct chain pairing. Here we report for the first time the identification of a Two‐in‐One antibody by yeast surface display (YSD) screening of chicken-derived immune libraries. The resulting antibody simultaneously targets the epidermal growth factor receptor (EGFR) and programmed death‐ligand 1 (PD-L1) at the same Fv fragment with two non-overlapping paratopes. The dual action Fab is capable of inhibiting EGFR signaling by binding to dimerization domain II as well as blocking the PD-1/PD-L1 interaction. Furthermore, the Two-in-One antibody demonstrates specific cellular binding properties on EGFR/PD-L1 double positive tumor cells. The presented strategy relies solely on screening of combinational immune-libraries and obviates the need for any additional CDR engineering as described in previous reports. Therefore, this study paves the way for further development of therapeutic antibodies derived from avian immunization with novel and tailor-made binding properties.
... Durvalumab is reported as a selective, high-affinity, human IgG1 monoclonal antibody that blocks PD-L1. It has been used for the treatment of NSCLC [12] and urothelial carcinoma [13]. Avelumab is a promising new therapeutic agent for patients with metastatic Merkel cell carcinoma that has also been used in the treatment of NSCLC [14]. ...
Article
Full-text available
Whether smokers respond to anti-cancer drugs differently than non-smokers remains controversial. The objective of this study is to explore whether the better response of the smokers is specific to therapy of anti-PD-1/PD-L1, anti-checkpoint inhibitor, individual drugs on the cell surface, or lung cancer. Our results showed that among all non-small cell lung cancer (NSCLC) patients, when the data from anti-PD-1/PD-L1, anti-CTLA-4, and anti-MUC1 drugs are combined, the mean hazard ratios (HR) of smokers and non-smokers were 0.751 and 1.016, respectively. A meta-analysis with a fixed effect (FE) model indicated that the smokers have an HR value of 0.023 lower than that of the non-smokers. A stratified subgroup meta-analysis indicated that when treated with anti-CTLA-4 drugs, smokers had reduced HR values of 0.152 and 0.165 on average and FE model meta-analysis, respectively. When treated with an anti-MUC1 drug, smokers had reduced HR values of 1.563 and 0.645, on average and FE model meta-analysis, respectively. When treated with a combination of nivolumab and ipilimumab drugs, smokers had, on average, reduced HR and FE model meta-analysis values (0.257 and 0.141), respectively. Smoking is a clinical response predictor for anti-PD/PD-L1 monotherapy or first-line treatment in lung, urothelial carcinoma, and head and neck cancer. Smokers treated with other drugs have shown worse responses in comparison to non-smokers. These data suggest that, along with the progress in the development of new drugs for cancer, drugs acting on specific genotypes of smokers likely will arise.
... Immunotherapy has provided new options for treating urothelial carcinomas but responses occur in less than one out of four patients treated with immune checkpoint blockade [24,25], frequently due to a non-inflamed tumor microenvironment. The percentage of PD-1 and/or PD-L1 has become critical biological predictive markers to consider the prescribe of such blockers. ...
Article
Full-text available
Recurrence and progression of non-muscle-invasive bladder cancer (NMIBC), frequent despite the availability of multiple treatment modalities, may be partly explained by the presence of immunosuppressive cell populations. We hypothesized that progression of disease could be prevented by the administration of an activated T cell immunotherapy (ACT) at time points when immunosuppressive populations increased in peripheral blood. In an N-of-1 study, a patient with multiple primary bladder high grade urothelial carcinomas, previously treated with standard local resection and chemotherapy but with evidence of progression, received ACT consisting of dendritic cells mixed with cytokine induced killer cells (DC/CIK), intravenously 18 times over a 6 year period at indicated time of observed increases in peripheral blood immunosuppressive CD8+/CD28- cells. Peripheral blood was analyzed for T cell phenotype by flow cytometry, T cell receptor (TCR) repertoire, and circulating tumor DNA (ctDNA) by next generation sequencing (NGS) at the time of each infusion. Cystoscopy and pelvic CT scans were performed at routine intervals to assess clinical status of disease. There has been no recurrence or metastasis of urothelial carcinoma. Peripheral blood cytotoxic T cells and unique TCR clones increased and suppressive T cell populations decreased after DC/CIK infusions evidenced by the two more proof-of concept cases. ctDNA analysis detected mutations in six genes (ARID1B, MYCN, CDH23, SETD2, NOTCH4 and FAT1) which appeared at different times, but all of them disappeared after the DC-CIK infusions. These data suggest that DC/CIK infusions may be associated with beneficial changes in T cell phenotype, TCR repertoire, decreases in circulating tumor DNA and sustained recurrence-free survival.
... Urothelial cancers (171) Unresectable stage III non-small cell lung cancer Atezolizumab ...
Article
Full-text available
The dawn of the 20th century saw the formative years of developments in immunology. In particular, immunochemistry, specifically pertaining to antibodies, was extensively studied. These studies laid the foundations for employing antibodies in a variety of ways. Not surprisingly, antibodies have been used for applications ranging from biomedical research to disease diagnostics and therapeutics to evaluation of immune responses during natural infection and those elicited by vaccines. Despite recent advancements in cellular immunology and the excitement of T cell therapy, use of antibodies represents a large proportion of immunotherapeutic approaches as well as clinical interventions. Polyclonal antibodies in the form of plasma or sera continue to be used to treat a number of diseases, including autoimmune disorders, cancers, and infectious diseases. Historically, antisera to toxins have been the longest serving biotherapeutics. In addition, intravenous immunoglobulins (IVIg) have been extensively used to treat not only immunodeficiency conditions but also autoimmune disorders. Beyond the simplistic suppositions of their action, the IVIg have also unraveled the immune regulatory and homeostatic ramifications of their use. The advent of monoclonal antibodies (MAbs), on the other hand, has provided a clear pathway for their development as drug molecules. MAbs have found a clear place in the treatment of cancers and extending lives and have been used in a variety of other conditions. In this review, we capture the important developments in the therapeutic applications of antibodies to alleviate disease, with a focus on some of the recent developments.
... ICIs induce durable responses and prolong the survival of patients with advanced cancers by blocking the activity of the co-inhibitory receptor, key to the T-cell immune response, and consequently promoting T-cell-mediated antitumor activity (3,4). Drugs targeting this negative immune regulatory pathway, including the anti-PD-1 monoclonal antibodies (mAbs) nivolumab (5), pembrolizumab (6), and cemiplimab (7) and the anti-PD-L1 mAbs atezolizumab (8), avelumab (9), and durvalumab (10) have been approved for the treatment of various cancer types. These agents have now become first-line and adjuvant therapies, particularly for the treatment of lung cancer. ...
Article
Full-text available
Antibodies against checkpoint inhibitors such as anti-programmed cell death protein 1 (PD-1) and its ligand anti-programmed death ligand 1 (PD-L1) have shown clinical efficacy in the treatment of multiple cancers. However, there are only a few studies on biomarkers for these targeted immunotherapies, especially in peripheral blood. We first studied the role of interferon-induced protein-10 (IP10) combined with interleukin-8 (IL-8) in peripheral blood as a biomarker of immune-combined chemotherapy for lung cancer and multiple cancers. We used the high-throughput cytokine detection platform and performed bioinformatics analysis of blood samples from 67 patients with lung cancer and 24 with multiple cancers. We selected the ratio of IP-10 to IL-8 (S2/S0, ratio of changes at 10–12 weeks after treatment to baseline) to predict the response to immunotherapy combined with chemotherapy and evaluate the survival of lung cancer patients and mixed cancer patients. In patients treated with the combination therapy, the specificity and sensitivity of IL-8 and IP10 together as predictors were improved compared with those of IL-8 and IP10 alone. Our conclusion was verified in not only lung cancer but also multiple cancer research cohorts. We then further validated the predictive effect of biomarkers in different histologic types of NSCLC and chemotherapy combined with different PD-1 drug groups. Subsequent validation should be conducted with a larger number of patients. The proposed marker IP10 (S2/S0)/IL-8 (S2/S0), as a predictive immunotherapy biomarker, has broad prospects for future clinical applications in treating patients with multiple intractable neoplasms.
Article
Full-text available
Glucose-regulated protein 94 (GRP94) is an endoplasmic reticulum (ER)-resident member of the heat shock protein 90 (HSP90) family. In physiological conditions, it plays a vital role in regulating biological functions, including chaperoning cellular proteins in the ER lumen, maintaining calcium homeostasis, and modulating immune system function. Recently, several reports have shown the functional role and clinical relevance of GRP94 overexpression in the progression and metastasis of several cancers. Therefore, the current review highlights GRP94’s physiological and pathophysiological roles in normal and cancer cells. Additionally, the unmet medical needs of small chemical inhibitors and the current development status of monoclonal antibodies specifically targeting GRP94 will be discussed to emphasize the importance of cell surface GRP94 as an emerging therapeutic target in monoclonal antibody therapy for cancer.
Article
Full-text available
Importance: The data reported herein were accepted for assessment by the US Food and Drug Administration for Biologics License Application under priority review to establish the clinical benefit of durvalumab as second-line therapy for locally advanced or metastatic urothelial carcinoma (UC), resulting in its recent US approval. Objective: To report a planned update of the safety and efficacy of durvalumab in patients with locally advanced/metastatic UC. Design, setting, and participants: This is an ongoing phase 1/2 open-label study of 191 adult patients with histologically or cytologically confirmed locally advanced/metastatic UC whose disease had progressed on, were ineligible for, or refused prior chemotherapy from 60 sites in 9 countries as reported herein. Intervention: Patients were administered durvalumab intravenous infusion, 10 mg/kg every 2 weeks, for up to 12 months or until progression, starting another anticancer therapy, or unacceptable toxic effects. Main outcomes and measures: Primary end points were safety and confirmed objective response rate (ORR) per blinded independent central review (Response Evaluation Criteria In Solid Tumors [RECIST], version 1.1). Results: A total of 191 patients with UC had received treatment. As of October 24, 2016 (90-day update), the median follow-up was 5.78 months (range, 0.4-25.9 months). The median age of patients was 67.0 years and most were male (136 [71.2%]) and white (123 [71.1%]). All patients had stage 4 disease, and 190 (99.5%) had prior anticancer therapy (182 [95.3%] postplatinum). The ORR was 17.8% (34 of 191; 95% CI, 12.7%-24.0%), including 7 complete responses. Responses were early (median time to response, 1.41 months), durable (median duration of response not reached), and observed regardless of programmed cell death ligand-1 (PD-L1) expression (ORR, 27.6% [n = 27; 95% CI, 19.0%-37.5%] and 5.1% [n = 4; 95% CI, 1.4%-12.5%] in patients with high and low or negative expression of PD-L1, respectively). Median progression-free survival and overall survival were 1.5 months (95% CI, 1.4-1.9 months) and 18.2 months (95% CI, 8.1 months to not estimable), respectively; the 1-year overall survival rate was 55% (95% CI, 44%-65%), as estimated by Kaplan-Meier method. Grade 3/4 treatment-related adverse events (AEs) occurred in 13 patients (6.8%); grade 3/4 immune-mediated AEs occurred in 4 patients (2.1%); and treatment-related AEs led to discontinuation of 3 patients (1.6%), 2 of whom had immune-mediated AEs that led to death (autoimmune hepatitis and pneumonitis). Conclusions and relevance: Durvalumab, 10 mg/kg every 2 weeks, demonstrates favorable clinical activity and an encouraging and manageable safety profile in patients with locally advanced/metastatic UC. Trial registration: clinicaltrials.gov Identifier: NCT01693562.
Article
Full-text available
PD-L1 and PD-L2 are ligands for the PD-1 immune inhibiting checkpoint that can be induced in tumors by interferon exposure, leading to immune evasion. This process is important for immunotherapy based on PD-1 blockade. We examined the specific molecules involved in interferon-induced signaling that regulates PD-L1 and PD-L2 expression in melanoma cells. These studies revealed that the interferon-gamma-JAK1/JAK2-STAT1/STAT2/STAT3-IRF1 axis primarily regulates PD-L1 expression, with IRF1 binding to its promoter. PD-L2 responded equally to interferon beta and gamma and is regulated through both IRF1 and STAT3, which bind to the PD-L2 promoter. Analysis of biopsy specimens from patients with melanoma confirmed interferon signature enrichment and upregulation of gene targets for STAT1/STAT2/STAT3 and IRF1 in anti-PD-1-responding tumors. Therefore, these studies map the signaling pathway of interferon-gamma-inducible PD-1 ligand expression.
Article
Full-text available
Purpose We assessed the safety and antitumor activity of avelumab, a fully human anti–programmed death-ligand 1 (PD-L1) IgG1 antibody, in patients with refractory metastatic urothelial carcinoma. Methods In this phase Ib, multicenter, expansion cohort, patients with urothelial carcinoma progressing after platinum-based chemotherapy and unselected for PD-L1 expression received avelumab 10 mg/kg intravenously every 2 weeks. The primary objectives were safety and tolerability. Secondary objectives included confirmed objective response rate (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1), progression-free survival, overall survival (OS), and PD-L1–associated clinical activity. PD-L1 positivity was defined as expression by immunohistochemistry on ≥ 5% of tumor cells. Results Forty-four patients were treated with avelumab and followed for a median of 16.5 months (interquartile range, 15.8 to 16.7 months). The data cutoff was March 19, 2016. The most frequent treatment-related adverse events of any grade were fatigue/asthenia (31.8%), infusion-related reaction (20.5%), and nausea (11.4%). Grades 3 to 4 treatment-related adverse events occurred in three patients (6.8%) and included asthenia, AST elevation, creatine phosphokinase elevation, and decreased appetite. The confirmed objective response rate by independent central review was 18.2% (95% CI, 8.2% to 32.7%; five complete responses and three partial responses). The median duration of response was not reached (95% CI, 12.1 weeks to not estimable), and responses were ongoing in six patients (75.0%), including four of five complete responses. Seven of eight responding patients had PD-L1–positive tumors. The median progression-free survival was 11.6 weeks (95% CI, 6.1 to 17.4 weeks); the median OS was 13.7 months (95% CI, 8.5 months to not estimable), with a 12-month OS rate of 54.3% (95% CI, 37.9% to 68.1%). Conclusion Avelumab was well tolerated and associated with durable responses and prolonged survival in patients with refractory metastatic UC.
Article
Full-text available
Background Patients with advanced urothelial carcinoma that progresses after platinum-based chemotherapy have a poor prognosis and limited treatment options. Methods In this open-label, international, phase 3 trial, we randomly assigned 542 patients with advanced urothelial cancer that recurred or progressed after platinum-based chemotherapy to receive pembrolizumab (a highly selective, humanized monoclonal IgG4κ isotype antibody against programmed death 1 [PD-1]) at a dose of 200 mg every 3 weeks or the investigator’s choice of chemotherapy with paclitaxel, docetaxel, or vinflunine. The coprimary end points were overall survival and progression-free survival, which were assessed among all patients and among patients who had a tumor PD-1 ligand (PD-L1) combined positive score (the percentage of PD-L1–expressing tumor and infiltrating immune cells relative to the total number of tumor cells) of 10% or more. Results The median overall survival in the total population was 10.3 months (95% confidence interval [CI], 8.0 to 11.8) in the pembrolizumab group, as compared with 7.4 months (95% CI, 6.1 to 8.3) in the chemotherapy group (hazard ratio for death, 0.73; 95% CI, 0.59 to 0.91; P=0.002). The median overall survival among patients who had a tumor PD-L1 combined positive score of 10% or more was 8.0 months (95% CI, 5.0 to 12.3) in the pembrolizumab group, as compared with 5.2 months (95% CI, 4.0 to 7.4) in the chemotherapy group (hazard ratio, 0.57; 95% CI, 0.37 to 0.88; P=0.005). There was no significant between-group difference in the duration of progression-free survival in the total population (hazard ratio for death or disease progression, 0.98; 95% CI, 0.81 to 1.19; P=0.42) or among patients who had a tumor PD-L1 combined positive score of 10% or more (hazard ratio, 0.89; 95% CI, 0.61 to 1.28; P=0.24). Fewer treatment-related adverse events of any grade were reported in the pembrolizumab group than in the chemotherapy group (60.9% vs. 90.2%); there were also fewer events of grade 3, 4, or 5 severity reported in the pembrolizumab group than in the chemotherapy group (15.0% vs. 49.4%). Conclusions Pembrolizumab was associated with significantly longer overall survival (by approximately 3 months) and with a lower rate of treatment-related adverse events than chemotherapy as second-line therapy for platinum-refractory advanced urothelial carcinoma. (Funded by Merck; KEYNOTE-045 ClinicalTrials.gov number, NCT02256436.)
Article
3012 Background: The immunosuppressive enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) facilitates immune tolerance in cancer via T-cell suppression, and IDO1 overexpression is associated with poor survival. Epacadostat, an oral inhibitor of IDO1, has been shown to be well tolerated as monotherapy and in combination with checkpoint inhibitors. ECHO-202/KEYNOTE-037 is a phase 1/2 study evaluating the safety and efficacy of oral epacadostat plus IV pembrolizumab in patients (pts) with advanced tumors. Based on phase 1 outcomes, epacadostat 100 mg BID plus pembrolizumab 200 mg Q3W was selected for phase 2 evaluation. This analysis summarizes phase 2 safety experience in the overall population of ECHO-202/KEYNOTE-037 (pooled across tumor types) at an October 29, 2016 data cutoff. Methods: Phase 2 pts were ≥18 years of age with advanced or recurrent melanoma (MEL), non–small cell lung cancer (NSCLC), renal cell carcinoma (RCC), urothelial carcinoma (UC), triple-negative breast cancer, squamous cell carcinoma of head and neck (SCCHN), ovarian cancer, diffuse large B-cell lymphoma, or microsatellite instability–high colorectal cancer. Results: The overall safety population comprised 244 pts receiving ≥1 study treatment dose. Median age was 63 years, 52% were women, and 91% were white. As of data cutoff, 134 study pts (55%) discontinued study treatment, primarily due to disease progression (n = 97). Median exposure to study treatment was 86 days (range, 1–374 days). TRAEs occurring in ≥5% of pts were fatigue (23%); rash (16%); diarrhea and nausea (7% each); increased alanine aminotransferase, increased aspartate aminotransferase, and pruritus (6% each); and pyrexia (5%). A total of 37 pts (15%) had grade ≥3 TRAEs; the most common grade ≥3 TRAEs were increased lipase (asymptomatic) and rash (3% each). TRAEs led to discontinuation in 3% of pts. Conclusions: Epacadostat 100 mg BID plus pembrolizumab 200 mg Q3W was associated with an acceptable safety profile in pts with advanced cancers, supporting continued evaluation of the combination. The phase 3 ECHO-301/KEYNOTE-252 MEL study is ongoing and additional phase 3 studies (NSCLC, UC, RCC, SCCHN) are planned. Clinical trial information: NCT02178722.
Article
8508 Background: Anti-PD-1 therapy produces objective and often durable responses in ~20% of unselected patients (pts) with metastatic non-small cell lung cancer (NSCLC). However, the role of PD-1 blockade in treating resectable NSCLC is unknown. This is the first study to test nivolumab in the neoadjuvant setting. This trial design provides an opportunity to examine anti-PD-1 mechanism of action and immunologic correlates of outcomes. Methods: Patients with Stage IB - IIIA NSCLC received 2 doses of nivolumab 3mg/kg over 4 weeks before surgery. The primary endpoint was safety in 20 patients with resected NSCLC. Efficacy was explored using objective pathologic response criteria. Correlative studies of the tumor immune microenvironment, tumor mutation and predicted neoantigen loads, and changes in T cell receptor (TCR) clonality in tumor and blood pre and post treatment were conducted. Results: 22 pts were treated. Nivolumab was well-tolerated and no surgeries were delayed. 1 pt withdrew from study preop without progression or toxicity. Among the 21 attempted resections, 1 tumor was unresectable. 9/21 (43%, 95% CI 24-63%) had a major pathologic response ( < 10% viable tumor cells in resection specimen). With a median postop follow-up of 9 months, 18 pts (86%) remain alive and recurrence free. Pre-treatment tumor exome sequencing showed a correlation between both tumor mutation and predicted neoantigen loads with pathologic response. Multiplex immunohistochemistry of pre- and post-treatment tumors showed an influx of PD-1+CD8+ T cells into responding tumors. TCR sequencing demonstrated that expanded peripheral T cell clones after treatment match clones found in the tumor. Conclusions: Neoadjuvant nivolumab in resectable NSCLC did not delay surgery. Major pathologic response rate was encouraging and compares favorably to outcomes with cisplatin-based neoadjuvant chemotherapy. Genomic analyses suggest that higher mutational and neoantigen burden could result in deeper pathologic response. Immunologic analyses support the detection of intra-tumoral T cell clones in the blood after treatment with nivolumab and may provide further insight into the molecular and immunologic features of response and non-response to PD-1 blockade. Clinical trial information: NCT02259621.
Article
6012 Background: Pembrolizumab has efficacy in metastatic HNSCC. We hypothesized that treatment intensification in surgically resectable HPV-negative, Stage III/IV HNSCC with neoadjuvant plus post-operative adjuvant (POA) pembrolizumab would be safe and reduce 1-year locoregional recurrence/distant metastases (LRR/DM) from 35% (historical: Cooper and Bernier NEJM 2004) to 15%. Methods: Phase II trial where all eligible patients received 1 dose of pembrolizumab (200 mg) prior to surgery and only those with high-risk pathologic features (HRPF: extracapsular extension/positive margin) were given POA cisplatin and radiation followed by pembrolizumab. PD-L1 staining was assessed by immunohistochemistry (9A11 antibody). Results: The study continues to enroll. Characteristics of 21 enrolled patients (pts) were median age 59 (32-87) yrs, tobacco use 81% (17 pts), clinical T2 (n = 2), T3 (n = 1), T4 (n = 18), and cN0/1 (n = 8), cN2 (n = 13). Preliminary analyses revealed five important findings: 1) No serious study drug-related AEs or unexpected surgical delays/complications, 2) No LRR/DM events in the first 10 patients with > 1-year follow-up after surgery 3) HRPF rate of 38% (95% CI: 18%-62%) (expected: 80%), 4) 43% of pts (95% CI: 22%-66%) with pathologic treatment response to neoadjuvant pembrolizumab (definition: tumor necrosis and/or giant cell/histiocytic reaction to keratinous debris in > 10% of tumor area), and 5) 48% of pts (95% CI:26%-70%) with clinical-to-pathologic downstaging. Pathologic treatment effect (TE) in ≥ 70% of the resected tumor or lymph node tissue area occurred in 6/21 pts (29%). Baseline tumor biopsies were PD-L1 positive ( > 1% of tumor cells) in 11/19 (58%) evaluable samples and in 7/8 (88%) evaluable pathologic responders. A significant correlation existed between baseline PD-L1 expression on tumor cells and pathologic treatment effect in the tumor (correlation coefficient: 0.72 and p = 0.0005). Conclusions: Neoadjuvant and adjuvant pembrolizumab was safe and well tolerated. We observed several lines of evidence supporting an anti-tumor effect in these pts with a single dose of pre-operative pembrolizumab. Further evaluation of this strategy is warranted. Clinical trial information: NCT02296684.
Article
Background Nivolumab has been associated with longer overall survival than docetaxel among patients with previously treated non–small-cell lung cancer (NSCLC). In an open-label phase 3 trial, we compared first-line nivolumab with chemotherapy in patients with programmed death ligand 1 (PD-L1)–positive NSCLC. Methods We randomly assigned, in a 1:1 ratio, patients with untreated stage IV or recurrent NSCLC and a PD-L1 tumor-expression level of 1% or more to receive nivolumab (administered intravenously at a dose of 3 mg per kilogram of body weight once every 2 weeks) or platinum-based chemotherapy (administered once every 3 weeks for up to six cycles). Patients receiving chemotherapy could cross over to receive nivolumab at the time of disease progression. The primary end point was progression-free survival, as assessed by means of blinded independent central review, among patients with a PD-L1 expression level of 5% or more. Results Among the 423 patients with a PD-L1 expression level of 5% or more, the median progression-free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30). A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy. Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy. Conclusions Nivolumab was not associated with significantly longer progression-free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals. (Funded by Bristol-Myers Squibb and others; CheckMate 026 ClinicalTrials.gov number, NCT02041533.)
Article
Immunogenicity depends on two key factors: antigenicity and adjuvanticity. The presence of exogenous or mutated antigens explains why infected cells and malignant cells can initiate an adaptive immune response provided that the cells also emit adjuvant signals as a consequence of cellular stress and death. Several infectious pathogens have devised strategies to control cell death and limit the emission of danger signals from dying cells, thereby avoiding immune recognition. Similarly, cancer cells often escape immunosurveillance owing to defects in the molecular machinery that underlies the release of endogenous adjuvants. Here, we review current knowledge on the mechanisms that underlie the activation of immune responses against dying cells and their pathophysiological relevance.