Industry corner: perspectives and controversies
Blinatumomab (Blincyto): lessons learned
from the bispecific t-cell engager (BiTE) in
acute lymphocytic leukemia (ALL)
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A BiTEV is a bispecific antibody construct with specificity for
CD3 on the T cell and a selected surface antigen on a tumor cell
[1]. When infused into patients, these antibodies are capable of
eliciting polyclonal T cell responses that are unrestricted by T cell
receptor specificity, presence of MHC class, or additional T cell
co-stimuli [2]. The most clinically advanced of these molecules is
R
the CD19/CD3 bispecific blinatumomab (BlincytoV), which was
approved for the treatment of adult relapsed/refractory (R/R)
Philadelphia negative (Ph-) B cell precursor ALL in the US and
EU in December 2014 and December 2015, respectively [3].
These approvals highlight the potential for a T-cell engaging ther-
apy in ALL patients, as well as the willingness of regulatory
authorities to swiftly advance such therapies via accelerated
mechanisms in orphan indications with significant unmet need.
Two years after these accelerated/conditional approvals in
relapsed/refractory ALL, randomized data confirmed that blina-
tumomab provided a statistically significant overall survival ad-
vantage compared to standard chemotherapy, nearly doubling
the median survival times [4].
The history of blinatumomab offers several biologic lessons that
may be useful when considering the future development of T-cell
engaging therapies. While some of these observations may prove
to be specific for CD19 or B cell targeting, others may be generaliz-
able across diseases and may reflect the biologic cascade initiated
upon T cell activation and CD3 engagement. We will discuss deliv-
ery rationale, toxicity management, ALL development and clinical
activity, and finally observed resistance patterns.
Rationale for administration schedule
The relatively small size of blinatumomab (55 kDa), and resulting
renal clearance, result in a short half-life of approximately 2 h in
humans [5]. Early clinical experience and T cell pharmacodynamics
suggested that sustained blinatumomab exposure were necessary
for safe and effective dosing, necessitating continuous IV infusion.
Initial phase 1 testing conducted in lymphoma patients revealed
that bolus administration generated significant neurologic toxicity
without antitumor effect, and these studies were terminated [6].
After switching to continuous IV administration, lymphoma pa-
tients were able to tolerate higher doses and antitumor activity was
observed. This lengthy dose exploration resulted in a shift to multi-
week continuous infusion delivery, a strategy that proved essential
in opening a therapeutic window for ALL and NHL.
One hypothesized explanation for this observation is that dis-
eased compartments beyond the bloodstream, where T cell density
C The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
V
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and effector–target ratio are low, require multi-week exposures to
drive tumor directed T cell activation, recruitment and expansion
[7, 8]. Pharmacodynamic studies of the blood during continuous
administration have characterized an early and rapid peripheral T
cell depletion (presumably due to redistribution), followed by nor-
malization to half baseline over 72 hours, and finally a polyclonal
expansion peaking at 18 6 9 days (to a mean of 220% 6 123%
relative to baseline) [9]. The most compelling clinical data sup-
porting a sustained 28-day cycle for ALL comes from a study in
pediatric patients, in which bone marrow examination was carried
out on days 15 and 28. Of 20 subjects who ultimately experienced a
complete response (CR) or a complete response with incomplete
hematologic recovery (CRh) in the first 28 days, only 8 (40%) had
achieved a CR/CRh by day 15, with the remainder having residual
leukemia (M3 or M2) or a hypocellular marrow until their day 28
evaluation. While most ALL patients across the larger studies
achieved CR/CRh did so after a single 28-day cycle of blinatumo-
mab, a subset (21% in adults, 26% in pediatrics) reached CR/CRh
only after a second cycle [10, 11]. Cycles longer than 28 days have
not been explored for ALL, but 2–3 additional cycles in patients
with minimal residual disease (MRD) or R/R disease were empiric-
ally allowed in clinical studies for patients who did not have alter-
native treatment options.
Cytokine release and neurotoxicity
Neurotoxicities, ranging from mild tremor to severe encephalop-
athy or seizure, have observed throughout the clinical develop-
ment of blinatumomab. Similar toxicities have subsequently
been described across several other CD19 targeting T cell thera-
pies and are likely to be class effects [12]. In the event of high-
grade neurotoxicities with blinatumomab, management has been
standardized to include temporary drug discontinuation and
prompt use of corticosteroids. As shown in Table 1, severe neuro-
toxicity adverse events have steadily declined as development
proceeded, likely attributable to the evolution and standardiza-
tion of clinical management.
Another potentially significant blinatumomab toxicity
observed in relapsed/refractory ALL (perhaps due to abundant
CD19 antigen load in such patients) is cytokine release syndrome.
In two patients treated in an early phase 2 study in R/R ALL,
Grade 4 cytokine release occurred (CTCAE criteria), prompting
mandatory cytoreduction and pretreatment steroids as part of
the treatment regimen [13]. Once these prophylactic measures
were included, no additional Grade 3/4 cases occurred in that
study, and steroid pretreatment became routine in the ALL treat-
ment paradigm. Severe cytokine release remains a rare but serious
complication of blinatumomab, with a 5% grade 3/4 AE rate
Industry corner Annals of Oncology

Table 1. Blinatumomab safety and efficacy of across three adult ALL studies
Phase 2 ‘206 Phase 2 ‘211 Phase 3 TOWER Phase 3 TOWER
blinatumomab6 blinatumomab7 blinatumomab4 chemotherapy

Demographics Patient Number (N ¼ xx) 36 189 271 134

1st salvage, late relapse 25% 0% 0% 0%
1st salvage <12 months 22% 20% 42% 49%
2nd salvageþ 53% 80% 58% 51%
Prior transplant 42% 34% 35% 34%
Safety Endpoints Neurologic AEs,Gr 3þ 14% 13% 9% 8%
Cytokine Release,Gr 3 þ (CTCAE) 6% (no premedication) 2% 5% 0%
Efficacy Endpoints CR/CRh/CRi* 69% 43% 44% 25%
CR 42% 33% 34% 16%
Median RFS (95% CI) 7.6 months (4.5–9.5) 5.9 months (4.8–8.3) 7.3 months (5.8–9.9) 4.6 months (1.8–19)
MRD- rate for CR** 88% 82% 76% 48%
Median OS (95% CI) 9.8 months (8.5–14.9) 6.1 months (4.2 to 7.5) 7.7 months (5.6–9.6) 4.0 months (2.9–5.3)

*Only CR/CRh was defined for studies 206 and 211.

**Minimal residual disease by PCR or flow cytometry as defined in study.

(again by CTCAE criteria) in 271 adult R/R ALL patients treated
in the Phase 3 TOWER study (Table 1) [4].
Adult acute lymphoblastic leukemia
development and clinical activity
Figure 1 provides a timeline of blinatumomab development in
adult ALL. After initial phase 1 work in mixed B-cell malignan-
cies, Micromet (the discoverer and original sponsor of bilantu-
momab development) launched a suite of dedicated ALL studies
in 2008–2010 [13, 14]. Based on promising pilot data, larger
single-armed phase 2 studies were launched shortly thereafter in
R/R disease (study ‘211), MRDþ disease (BLAST study), and R/R
Philadelphiaþ ALL (ALCANTARA study) to generate potential
pivotal datasets. After the 2012 acquisition by Amgen, a random-
ized phase 3 confirmatory study in R/R Philadelphia-ALL
(TOWER study) was initiated in 2013 to compare blinatumomab
with standard chemotherapy. Great efforts were made in the inte-
gration process to keep the former Micromet research and devel-
opment organization largely intact to minimize timeline delays
for clinical and preclinical programs.
Breakthrough designation and accelerated approval in the US,
along with a conditional approval in the EU, were ultimately
granted based upon data from the 189 patient, single-arm phase 2
R/R ‘211 study in adult ALL, with a 43% CR/CRh rate in this trial
[10]. Of those who achieved a CR/CRh, 82% were MRD- re-
sponders, and 40% went on to receive a stem cell transplant. The
confirmatory TOWER study in this same ALL population was
stopped early for efficacy in February of 2016, noting an improved

US breakthrough status
June 2014
EU conditional approval
Dec 2015 (R/R/ALL)
US IND filed US accelerated approval
2006 Dec 2014 (R/R/ALL)

2000 2002 2004 2006 2008 2010 2012 2014 2015 2016

2001 2004 2008 2010 2013 Feb 2016

Phase 1 study Phase 1 study Ph 2 study Ph 2 ‘206 study Ph 2 study TOWER study DMC stops
(short infusion) (continuous infusion) (MRD+) (R/R) (Ph+) Study early for efficacy
2010 2013
Ph 2 BLAST study Ph 3 TOWER study
(Pivotal MRD+) (Confirmatory R/R)
US regulatory event
EU regulatory event
2011
Clinical study Ph 2 ‘211 study
(Pivotal R/R)
Press release

Figure 1. Blinatumomab adult acute lymphoblastic leukemia development timeline.

2010 | Friberg and Reese Volume 28 | Issue 8 | 2017

Annals of Oncology
median overall survival as compared to standard of care chemo-
therapy at 7.7 versus 4.0 months (P ¼ 0.01) [4]. These data are cur-
rently under regulatory review in the US and EU. Each of these
studies included R/R ALL patients with relatively unfavorable
prognoses, with most having failed at least two prior inductions
(2nd salvageþ) and over 1/3 having had a prior stem cell trans-
plant. Each trial excluded patients who relapsed >12 months after
their first CR. These ‘late relapses’ are known to have a relatively
better prognosis, and indeed all such patients treated on the earlier
‘206 study (n ¼ 6 without stem cell transplant) responded to blina-
tumomab (5 CR, 1 CRh) [13]. Clinical activity across adult R/R
studies is summarized in Table 1.
Resistance patterns
In evaluating the totality of the data, blinatumomab activity ap-
pears to be greater in patients with lower disease burden. In the
‘211 R/R study, for example, while the overall CR/CRh rate was
43%, it was 29% for patients with >50% marrow involvement
and 73% with <50% marrow involvement [10]. While a
blinatumomab-specific mechanism underlying this observation
is not known, directional patterns of similar proportion were
observed in the both arms of the TOWER study, suggesting the
finding may be partly prognostic in nature [4]. For patients
whose detectable leukemia exists only as minimal residual disease
(MRD), the MRD negativity rate after one cycle of blinatumomab
treatment was 80% [15]. Together these data suggest that blinatu-
R
momab, and potentially other BiTEV therapies, may be most ef-
fective when deployed in cytoreduced and MRDþ settings.
Patterns of relapse and resistance appear to be multifactorial,
with available data supporting a variety of tumor, host, and com-
partmental mechanisms. Preclinical evidence indicates that
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BiTEV effectiveness can be blunted by tumor upregulation of fac-
tors such as PD-L1 or IDO; such mechanisms may be mitigated
in vitro by the addition of anti-PD1 antibodies or higher bispe-
cific antibody doses [16, 17]. Tumor upregulation of PD-L1 has
also been described in vivo in sequential marrow biopsies from an
ALL patients with primary blinatumomab resistance, lending fur-
ther credibility to the hypothesis that PD-L1 upregulation repre-
sents a mechanism of resistance [18].
Several informative clinical data points can be captured from
long-term follow-up of 21 MRDþ ALL patients treated with bli-
natumomab [15]. Of these patients, two ultimately relapsed with
extramedullary disease (1 testicular and 1 CNS) and two relapsed
with CD19 negative ALL. While these represent a minority of pa-
tients, they demonstrate that target loss and compartmental es-
cape can also play roles in resistance. Long-term follow-up is now
available for these same subjects. Of the 16 patients who achieved
MRD negativity, 10 remained relapse free after a median follow-
up of 50.8 months (including 5 who did not receive subsequent
transplant or anti-leukemic therapy) [19].
Future development and unanswered
questions
Blinatumomab in ALL has provided clear proof of concept that a
bispecific antibody can engage a host’s immune system,
Volume 28 | Issue 8 | 2017
Industry corner
promoting the expansion of T cells and selective attack of CD19
expressing tumor cells. Ongoing clinical studies are targeting of B
cell malignancies in settings of measured or presumed MRD, and
are testing combinations with pembrolizumab to potentially cir-
cumvent mechanisms of resistance. Unanswered questions re-
main as to how broadly effective this platform technology will
prove to be beyond CD19, and whether solid tumors will be sus-
R
ceptible to BiTEV molecules at tolerable dose levels. Similarly, it is
unknown how engineering efforts to elongate the half-life of these
and other bispecifics might alter the therapeutic window of such
constructs, for better or for worse. These unanswered questions
are being explored by multiple sponsors in the clinic, and will
surely remain areas of active research for years to come.
G. Friberg* & D. Reese
Translational Sciences, Amgen, Inc, Thousand Oaks, California, USA
(*E-mail: gfriberg@amgen.com)
Acknowledgements
The authors would like express their gratitude to the patients,
their families, and the investigators who have participated in the
clinical studies discussed.
Funding
None declared.
Disclosure
The authors are employees and shareholders of Amgen.
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Published online 31 March 2017
Volume 28 | Issue 8 | 2017