Cancer Treatment Reviews 67 (2018) 10–20

Contents lists available at ScienceDirect

Cancer Treatment Reviews

journal homepage: www.elsevier.com/locate/ctrv

Anti-Tumour Treatment

Treatment of advanced HER2-positive breast cancer: 2018 and beyond T

a,⁎ b c d e
Noam Pondé , Mariana Brandão , Georges El-Hachem , Emilie Werbrouck , Martine Piccart
a
Academic Promoting Team, Institut Jules Bordet, Blvd de Waterloo 121, 7th Floor., 1000 Brussels, Belgium
b
Academic Promoting Team, Institut Jules Bordet, Belgium
c
Medical Department, Institut Jules Bordet, Belgium
d
Medical Oncology Department, University Hospital Leuven, Belgium
e
Research Department, Institut Jules Bordet, Belgium

A R T I C LE I N FO A B S T R A C T

Keywords: In the 1980s the importance of HER2 signalling to the aberrant behaviour of a subset of breast cancer cells was
Advanced breast cancer recognized for the first time and, consequently, a hitherto unknown subtype of breast cancer – HER2-positive
HER2-positive disease (HER2+) breast cancer was identified. The development of the anti-HER2 class of drugs, first with trastuzumab,
Anti-HER2 treatment followed closely by lapatinib, pertuzumab, and T-DM1, has improved outcomes dramatically. Nevertheless,
metastatic HER2+ breast cancer remains an incurable disease and new therapeutic options are needed.
Additionally, the rapid changes in treatment standards 5 years ago have left unanswered numerous questions,
including the “real-life” benefit of pertuzumab and T-DM1, since both the CLEOPATRA and EMILIA trials were
conducted in populations that no longer exist in practice and, moreover, on the role of endocrine therapy in
HER2+ disease. Furthermore, despite significant research efforts, including translational efforts and new ima-
ging techniques, no predictive biomarkers have been clinically validated and therefore a more refined approach
to treatment tailoring remains beyond our reach. Finally, a better understanding of resistance to currently ex-
isting anti-HER2 agents and of the role played by the microenvironment (e.g. immune system) and of inter-
connected signalling pathways (e.g. PI3K-mTOR-AKT) is at the core of clinical trials exploring new drugs and
new regimens. These include the combination of anti-HER2 agents and anti-PD-1/PDL-1, PI3K inhibitors and
CDK 4/6 inhibitors, as well as a host of new panHER inhibitors, drug antibody conjugates and anti-HER anti-
bodies, which may, in coming years further push the boundaries of what we can do for our patients.

Introduction management, open research questions, the state of predictive bio-

The aberrant behaviour of cancer relies on the subversion of growth
signalling receptors and pathways [1]. In breast cancer (BC), human
epidermal growth factor receptor 2 (HER2) is especially relevant [2].
BC that overexpresses HER2 (HER2+) forms a subpopulation
amounting to 15–20% of cases, with an aggressive clinical behaviour
[3]. Intense research efforts have yielded, starting with trastuzumab, a
class of anti-HER2 agents that includes today 4 approved agents in the
advanced setting – trastuzumab, lapatinib, pertuzumab and T-DM1.
These agents have doubled median overall survival (OS) – today sur-
passing 50 months, and more than tripled the 5-year survival rate [4]. A
number of research questions, however, remain open on the best se-
quencing of available regimens, on how to treat estrogen receptor po-
sitive (ER+)/HER2+ disease, as well as on how to improve treatment
tailoring for the individual patient.
This review will provide an updated look at all current aspects of the
evolving field of advanced HER2+ BC (MBC), covering current
marker development, as well as ongoing drug development efforts
aiming at further improving patient outcomes.
Current management of HER2+ advanced disease
According to international guidelines, patients with metastatic
HER2-positive BC (MBC) should be stratified according to prior ex-
posure to trastuzumab and time elapsed between last dose and disease
relapse [5,6]. Table 1 summarizes the results of key trials determining
current standards and Fig. 1 summarizes guideline recommendations.
Most patients should receive anti-HER2 therapy associated with
chemotherapy [5,6]. Patients who have not been exposed to trastu-
zumab or who develop metastatic disease 6 months after adjuvant
trastuzumab are candidates for first line treatment with a taxane,
trastuzumab and pertuzumab [7,8]. However, if disease progression
occurs while on trastuzumab or with a treatment free interval of less
than 6 months, direct second line treatment with T-DM1 is likely the

⁎
Corresponding author.
E-mail address: Noam.ponde@bordet.be (N. Pondé).

https://doi.org/10.1016/j.ctrv.2018.04.016
Received 28 February 2018; Received in revised form 6 April 2018; Accepted 9 April 2018
0305-7372/ © 2018 Elsevier Ltd. All rights reserved.
N. Pondé et al. Cancer Treatment Reviews 67 (2018) 10–20

Table 1
Results of key trials determining clinical practice in advanced/metastatic HER2+ disease.
Trial ClinicalTrials.gov Nb. of Line of treatment (advanced setting) Treatment arms (control vs. Results (control vs. experimental)
number patients experimental)
PFS OS

CLEOPATRA NCT00567190 808 1st line; TFI > 12 months Docetaxel + Trastuzumab vs. 12.4 m vs. 18.7 m 40.8 m vs. 56.5 m
Docetaxel + Trastuzumab + HR 0.68 (95% CI HR 0.68 (95% CI
Pertuzumab 0.58–0.80) 0.56–0.84)
EMILIA NCT00829166 991 2nd line (after progression on Capecitabine + Lapatinib vs. 6.4 m vs. 9.6 m 25.9 m vs. 29.9 m
trastuzumab and taxane) or T-DM1 HR 0.65 (95% CI HR 0.75 (95% CI
TFI < 6 months 0.55–0.77) 0.64–0.88)
TH3RESA NCT01419197 602 ≥2nd line (after progression on Treatment of physician’s choice vs. T- 3.3 m vs. 6.2 m 15.8 m vs. 22.7 m
taxane, trastuzumab and lapatinib) DM1 HR 0.53 (95% CI HR 0.68 (95% CI
0.42–0.66) 0.54–0.85)

Geyer et al. NCT00078572 399 ≥2nd line (after progression on Capecitabine vs. 4.3 m vs. 6.2 m 15.3 m vs. 15.6 m
trastuzumab, taxane and Capecitabine plus Lapatinib HR 0.57 (95% CI HR 0.78 (95% CI
anthracycline) 0.43–0.77) 0.55–1.12)
EGF104900 NCT00320385 296 ≥2nd line (after progression on Lapatinib vs. 8 weeks vs. 11 10 vs. 14 months
trastuzumab) Lapatinib + Trastuzumab weeks HR 0.75 (95% CI
HR 0.73 (95% CI 0.53–1.07)
0.57–0.93)

Abbreviations: m: months; OS: median overall survival; ORR: overall response ratio; PFS: median progression free survival; T-DM1: adotrastuzumab emtansine; TFI:
trastuzumab-free interval (in the neoadjuvant or adjuvant setting).

Fig. 1. Current advanced HER2-positive breast cancer treatment guidelines.

best option [9–11]. Patients who have received first line treatment as
per the CLEOPATRA trial, are candidates for T-DM1 in second line [6].
Following the use of T-DM1, lapatinib containing combinations or
chemotherapy + trastuzumab are standard options, though sequencing
is not clear as these regimens were developed before the use of pertu-
zumab and T-DM1 [12–14]. Finally patients who do not receive T-DM1
in first or second line can receive it in third line or more [15,16].
Open research questions in 2018
What is the efficacy of pertuzumab in trastuzumab – pre-treated “real life”
populations?
Only 23% of patients in CLEOPATRA received adjuvant trastu-
zumab, which is strikingly different from “real life” clinical practice
[17]. These pre-treated patients had to have trastuzumab-free interval
greater than 12 months in order to participate but, even so, presented
worse PFS compared to trastuzumab-naïve patients, both in the pertu-
zumab-arm (16.9 vs. 21.6 months) and in the control-arm (10.4 vs.
12.6 months), when compared to patients with de novo disease. They
seemed, nevertheless, to derive benefit from the dual blockade (median
PFS of 16.9 vs. 10.4 months in the control arm). This difference in
outcomes may be due to the development of trastuzumab-resistant
disease, but the impact of resistance on the response to the combination
of trastuzumab with pertuzumab is not fully understood.
Further data comes from the PHEREXA trial evaluating dual
blockade with pertuzumab + trastuzumab + capecitabine for patients
previously treated with a taxane and trastuzumab in the metastatic
setting. Results show no improvement in median PFS with the addition
of pertuzumab (11.1 vs. 9.0 months, HR 0.82; 95% CI 0.65–1.02) [18],
but better median OS (36.1 vs. 28.1 months; HR 0.68, 95% CI
0.51–0.90). A similar trend towards diminished benefit in trastuzumab
pre-treated patients comes from a preliminary analysis of the SUPER
trial, which tested the CLEOPATRA regimen in 248 patients, 62.5% of
which had received adjuvant trastuzumab (median PFS of 17.3 months
for the trastuzumab naïve vs 14.9 months for the trastuzumab pre-
treated) [19]. Additionally, a small case series with 35 patients treated
with trastuzumab in the (neo)adjuvant setting and who received first-
line therapy with trastuzumab + pertuzumab + docetaxel showed a
median PFS of 12 months (95% CI 2–38), and a median OS of only
15.2 months (95% CI 2–36), which is strikingly lower than the
56.5 months observed in CLEOPATRA [20].
These few data suggest that the “real life” benefit from dual
blockade in trastuzumab pre-treated patients is smaller than what was
seen in CLEOPATRA. In the near future, the results of trials such as
PERUSE (NCT01572038) as well as national registries such as SystHERs
(NCT01615068), SAMANTHA (NCT02913456) and HER2-OBS are
likely to resolve this question [21].

11
N. Pondé et al.
What is the efficacy of T-DM1 in pertuzumab – pre-treated “real life”
populations?
EMILIA and TH3RESA did not include patients pre-treated with
pertuzumab, which is now standard in the first-line metastatic setting
and an option in the (neo)adjuvant setting. Observational studies have
reported the activity of T-DM1 in patients previously exposed to per-
tuzumab. In a series of 78 patients, tumour response rate (RR) was 18%
(95% CI 9–26%), a third of patients received T-DM1 ≥ 6 months and
the overall median duration on therapy was 4.0 months. In another
larger series, with 250 patients, 19% (n = 47) received prior pertu-
zumab + trastuzumab + taxane treatment [22]. Comparing pertu-
zumab pre-treated vs. naïve-patients, there were no significant differ-
ences in response rate (40.2% vs. 44.3% respectively, p = 0.75),
median PFS (4 vs. 6 months, p = 0.13) or median OS (17 vs. 22 months,
p = 0.27). However, survival in the pertuzumab-treated group was
much lower than in the EMILIA trial (median PFS 9.6 months, median
OS 29.9 months). Finally, a small series of 34 patients who received
second-line T-DM1 after pertuzumab + trastuzumab were compared
with those who received only trastuzumab (n = 73). Results show
worse RR (33.3 vs. 57.1% respectively) and shorter median PFS (5.0 vs.
11.0 months: HR 2.02; 95% CI 1.14–3.58) in the pertuzumab pre-
treated cohort [23]. Therefore, available data suggests some efficacy,
though not comparable to the improvement in outcomes seen in
EMILIA. The results of the aforementioned registry studies should
provide valuable data to better resolve this issue.
What is the role of lapatinib in the pertuzumab/T-DM1 era?
Lapatinib trials were performed in the pre-pertuzumab and pre-T-
DM1 era, thus none of them included patients treated with these agents.
Today, lapatinib-based combinations are usually prescribed in the 3rd
line or beyond, with undefined benefit. A case series including 29 pa-
tients who received lapatinib after prior pertuzumab or T-DM1 (target
cohort) was compared to 445 patients (comparison cohort) who re-
ceived lapatinib and were pertuzumab and T-DM1-naïve [24]. Median
duration of treatment was 4.9 vs. 5.6 months respectively. Median time
to progression was 4.9 months (95%CI 3.0–7.6) in the target cohort and
5.7 months (95%CI 0.0–82.3) in the comparison cohort. In addition,
median OS was 23.9 months (95%CI 20.5-not reached) in the target
cohort and 25.8 months (95%CI 23.1–30.6) in the comparison cohort.
These results suggest clinically relevant benefit with lapatinib even in
pertuzumab/T-DM1 pretreated groups providing a small amount of
support to its current place in guidelines. In the future, a number of
trials with new anti-HER2 agents, such as SYD-985 (TULIP –
NCT03262935) or neratinib (NALA-NCT01808573) comparing these
agents in third line with capecitabine + lapatinib will prospectively
clarify the benefit of this combination.
Should elderly patients with advanced HER2+ disease be managed
differently?
Elderly (70 years or older) patients comprise a substantial propor-
tion of patients diagnosed with breast cancer today, and demographic
trends only suggest that elderly patients will become even more fre-
quent in the next few decades [25].
In principle, treatment decisions should not be made taking into
consideration age as the sole factor. Elderly patients should be eval-
uated before and during cancer treatment with comprehensive geriatric
assessment (CGA), and the results of this should be a key part of deci-
sion making [26]. Data on the efficacy, and even more importantly,
tolerability of anti-HER2 agents in this population is, however, sparse.
Elderly patients are historically underrepresented in clinical trials and
the most commonly used end-points and safety assessment methods
very often ignore important issues for elderly patients [27,28]. What
little data is available, coming from small case series, retrospective
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Cancer Treatment Reviews 67 (2018) 10–20
cohort studies and subanalysis of phase III trials suggest that as a whole,
anti-HER2 agents have similar efficacy in elderly patients, but are
nevertheless more toxic [29–32].
Recently, a trial exploring an elderly-specific treatment strategy has
presented its initial results. The EORTC 75111-10114 trial randomised
80 elderly, and more importantly, frail patients with HER2-positive
advanced breast cancer to receive pertuzumab + trastuzumab or per-
tuzumab + trastuzumab + metronomic cyclophosphamide. Results
suggest that these population benefit from dual blockade and that,
moreover, chemotherapy is a very important component of treatment
(PFS at 6 months for the no-chemotherapy arm was 46.2% vs 73.4%,
HR 0.65 {95% CI 0.37–1.12} p = 0.12). Safety outcomes suggest that
both strategies have similar incidence of grade 3–5 adverse events
(approximately 50%), and therefore toxicity is not negligible in this
population [33].
Existing data, therefore, suggests that elderly patients can and
should receive anti-HER2 treatment, albeit within a specific geriatric
environment and with careful follow-up.
Are T-DM1 and pertuzumab cost effective?
In order to assess the clinical value or benefit of new drugs, ESMO
has developed a “Magnitude of Clinical Benefit Scale” (ESMO-MCBS)
that evaluates the drug’s improvement both in survival and in QoL and
is graded from 1 (minimal benefit) to 5 (maximal benefit) in the ad-
vanced setting [34]. As an example, pertuzumab (in addition to tras-
tuzumab and docetaxel) in first-line gets an ESMO-MCBS score of 4 (out
of a possible 5), lapatinib + trastuzumab in third line a 4, lapa-
tinib + capecitabine in second line a 3 and T-DM1 in second-line re-
ceives an ESMO-MCBS score of 4. It is also important to mention that
other models of evaluating the clinical usefulness of therapeutic regi-
mens exist, such as NCCN evidence block models or the ASCO value
framework. Nevertheless, the expense associated with these drugs has
led to questions regarding their cost-effectiveness. The cost-effective-
ness of pertuzumab was evaluated in an US study which showed that its
combination to trastuzumab and docetaxel in the first-line metastatic
setting led to an additional 1.8 life-years gained, or 0.62 quality-ad-
justed life years (QALYs), with a total cost of $294 747 per patient,
which corresponds to $472 668 per QALY gained [35]. In an analysis
conducted for the United Kingdom’s National Institute for Health and
Care Excellence (NICE), that sets up its willingness to pay at £30,000
(approximately $46,000) per QALY, this combination had a 0% prob-
ability of being cost-effective when compared with trastu-
zumab + docetaxel [36]. A similar analysis performed on T-DM1,
comparing it to capecitabine + lapatinib in the 2nd line setting showed
that T-DM1 presented an incremental cost-effectiveness ratio (ICER) of
$183 828 per QALY [37]. In an analysis conducted for NICE, the ICER
was £167 236, which deemed the drug not cost-effective [38].
Interestingly, a recent study focused not on particular regimens but
on the sequencing of anti-HER2 treatment and compared the cost-ef-
fectiveness of different strategies [39]. The standard strategy of com-
bining trastuzumab + pertuzumab + docetaxel as 1st line therapy,
followed by T-DM1 (2nd line) and lapatinib + capecitabine (3rd line)
indeed resulted in the greater number of QALYs: 1.81. However, that
was achieved at a cost of $335 231 per patient, which corresponds to
$185 210 per QUALY. The sequence of trastuzumab + docetaxel as 1st
line treatment, followed by trastuzumab + lapatinib (2nd line) and
trastuzumab + capecitabine (3rd line), with no pertuzumab or T-DM1,
generated 1.41 QALYs, at a cost of $175 241 per patient. Finally,
trastuzumab + docetaxel as 1st line, T-DM1 as 2nd line and trastu-
zumab + lapatinib as 3rd line therapy was the least clinically effective
sequence (1.27 QALYs) but it was also the most cost-effective ($149
250, corresponding to $117 520/QALY). These results suggests that the
added clinical value of incorporating pertuzumab in the 1st line therapy
carries, at the same time, a 58% increase in the cost per QUALY and a
2.3-fold rise in the total cost of treatment. Thus, the cost-effectiveness of
N. Pondé et al.
current standards of care is far from well established, however bene-
ficial they can prove to individual patients.
Triple positive disease
Gene expression studies have clearly demonstrated in recent years
that HER2+ BC is a heterogeneous disease. Though HER2-enriched
subtype is more common, especially among ER- tumours, luminal
subtypes also make up a significant number of cases [40]. In these ER+
luminal tumours, preclinical evidence suggests intense interconnection
between the ER and HER2 signalling pathways, that the ER pathway is
one of the mechanisms of resistance to anti-HER2 therapy and that,
from a genomic/transcriptomic stand point, ER+/HER2+ tumours are
much more commonly luminal than ER-/HER2+ tumours, and have
both lower number of TILs and reduced PD-L1 expression [41,42].
Current treatment guidelines, however, do not propose distinct man-
agement strategies for ER+ and ER− HER2+ BC [5,6], partly due to
lacklustre results of initial trials testing ET in HER2+ patients, in-
cluding TAnDEM, eLEcTRA and EGF107692, relegating the strategy
either to patients who could not tolerate chemotherapy or to post
chemotherapy empirical “maintenance strategies“ [43–45].
More recent trials have rekindled interest in ET strategies and
brought forth additional data. PERTAIN tested first line le-
trozole + trastuzumab + pertuzumab vs letrozole + trastuzumab, with
or without induction docetaxel (as per physician’s choice), in 258 pa-
tients. PFS results showed a small, yet statistically significant, ad-
vantage to the dual blockade regimen (18 vs 15.8 months, HR 0.65,
95% IC 0.48–0.89, p = 0.0070) [46]. Though this trial did not compare
a chemotherapy backbone with an ET backbone, results diminish an-
xiety over this chemotherapy-free option. The mild toxicity profile is
also significant for “maintenance” strategies. Further new data comes
from the ALTERNATIVE trial, which tested dual blockade with trastu-
zumab + lapatinib + aromatase inhibitor (AI) vs AI + trastuzumab or
AI + lapatinib in second line or more. With 355 patients randomised,
the PFS results show increased and significant benefit with dual
blockade (11 m vs 5.7 m vs 8.3 m, respectively), though toxicity was
slightly increased with the use of dual blockade [47].
These data suggests that maintenance strategies after docetaxel in
first line are safe and that though no randomised studies prove the
strategy is superior to dual blockade alone, it remains valid in ER+
patients following induction chemotherapy. Furthermore, ER+ pa-
tients without a clear indication for chemotherapy can have good
outcomes with ET+ dual blockade alone. Lastly, for ER+ patients
having already received 2 lines of anti-HER2 therapy, dual
blockade + ET is an effective option. Further advance in the near future
is likely to come via the development of combined ET + anti-
HER + CDK 4/6 inhibitors regimens, which are currently being eval-
uated in multiple trials.
Predictive biomarkers in advanced HER2+ disease
The existence of primary and secondary resistance to anti-HER2
therapy, as well as the toxicity and expense related to these agents,
have greatly increased the interest surrounding predictive biomarkers
[35,48]. Unfortunately, however, no predictive biomarker has been
validated for clinical use and, today, the use of anti-HER2 agents is still
determined on the basis of HER2 status alone [49].
A number of putative biomarkers have been explored [50], in-
cluding HER2 itself (different expression, copy number, mutations), co-
ligands (HER2, EGFR, IGFR), downstream pathways (PIK3CA), stromal
components (TILs) and host factors (FCyR polymorphisms) [50]. This
“failure to thrive” in biomarker development is caused by the complex
nature of the underlying science itself and the difficult process of taking
a biomarker from bench into clinic [48,51]. It is alarming to note that
extensive retrospective research, conducted mostly on primary tumour
tissue samples (or on a few metastatic biopsies) in large trials such as
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Cancer Treatment Reviews 67 (2018) 10–20
CLEOPATRA, EMILIA, TH3RESA (and others) has been unproductive,
for the most part [52–54].
“Liquid biopsy” techniques, notably circulating tumour DNA
(ctDNA), hold the promise of analysing a more representative sample of
the heterogeneous and dynamic nature of cancer genome [55]. Two
recent phase I/II trials with newer anti-HER2 agents have explored
ctDNA. The MutHER trial [56], tested neratinib in advanced HER2-
negative patients harbouring HER2 mutations (HER2mut) tested in
tissue. Sixteen patients received neratinib. Results show a clinical
benefit rate (CBR) of 31% and a median PFS of 16 weeks. A sub-cohort
(N = 14) of these patients were tested for ctDNA at 3 different time
points (baseline, 4 weeks and progression). At baseline, 11 out of 14
had the same HER2mut in both tissue and ctDNA. Interestingly, a re-
duction on variant allele fraction (VAF) at week 4 correlated with drug
activity and PFS. Likewise, an increase in VAF correlated with pro-
gression [56]. A second study testing the panHER2 inhibitor pyrotinib
enrolled 38 patients [57] with advanced HER2-positive BC exposed to
at least 2 previous lines of anti-HER2 therapy. CBR rate was 61.1%.
Tissue and ctDNA were evaluated for biomarker research and results
suggest that PIK3CA and TP53 mutations in ctDNA, but not on tumour
tissue predict response. Though limited, these results suggest the po-
tential of ctDNA in advancing biomarker research.
Functional imaging in advanced HER2+ disease
Heterogeneity of HER2 over-expression limits the value of in-
dividual tumour biopsies and underscores the need for accurate tools
for whole body assessment of HER2 status. This has led to the testing of
paired targeting moieties with radioisotopes such at zirconium-89
(89Zr) for PET and indium-111 (111In) for single-photon emission CT
(SPECT), which accumulate in tumours over-expressing HER-2
[58–61].
The ZEPHIR study tested this strategy using 89Zr-trastuzumab
(HER2-PET) and early serial FDG–PET imaging, obtained in patients
with HER2-positive metastatic breast cancer who were candidates to
receive T-DM1. Patients found to have a negative HER2-PET and stable
or metabolic progression after one cycle of T-DM1 did not respond
thereafter, defining a negative predictive value (NPV) of 100%. When
baseline HER2 imaging was combined with early FDG–PET, the positive
predictive value (PPV) for response after three cycles was 100%.
Additionally this modality of combining the 2 metabolic imaging was
able to predict time to treatment failure (TTF). The median TTF in the
subgroup of patients who had a positive HER2 imaging and early FDG
metabolic response was 15 months (95% CI 9.7–not evaluable),
whereas it was only 2.8 months (95% CI 1.4–7.6) in those with negative
HER2 imaging and stable or progressive disease on early FDG–PET
[62]. This potential strategy for improved treatment tailoring warrants
independent validation.
New drugs & treatment strategies
Immunotherapy agents & combinations
HER2-enriched tumours are considered immunogenic, with a higher
mutational burden (2.05 mutations per Mb) when compared to luminal
tumours (between 0.84 and 1.38 mutations per Mb) [63,64] and a
significant rate of (close to 50% in some datasets) PD-L1 positivity
[65,66]. Preclinical models suggest a synergistic effect of anti-PD-1
agents on trastuzumab therapy in HER2+ tumours [67]. Taken to-
gether with the recent successes of immunotherapy in other solid tu-
mours, this has led to several clinical trials testing anti-PD-(L)1 agents
in advanced HER2+ BC (Fig. 2 and Table 2).
PANACEA, the first phase Ib/II trial evaluating the addition of
pembrolizumab to trastuzumab in trastuzumab-resistant HER2+ pa-
tients included 40 patients with PD-L1 positive tumours and a second
cohort of 12 patients with PD-L1 negative tumours [68]. 29% had
N. Pondé et al.
Fig. 2. New drugs & new strategies in combination with anti-HER2.
received prior pertuzumab, 72% prior T-DM1 and 40% prior lapatinib;
all of them had received prior anthracyclines and taxanes. Results,
however, proved disappointing in the PD-L1+ cohort, with a RR of
15% and a disease control rate (DCR) of 25%. No responses were seen
in the PD-L1 negative cohort. It is important to stress, however, that the
levels of TILs were low in collected metastatic samples: median stromal
TILs of patients in the PD-L1+ cohort was just 2% (mean: 8.1%, range:
0–40%) and 0% (mean: 1.2%, range: 0–5%) in the PD-L1 negative co-
hort. Interestingly, in patients who had TILs ≥ 5% (who are 41% of the
PD-L1+ cohort), RR was more encouraging (39%). In the PD-L1+
cohort, the median PFS was 2.7 months and the median OS was
16.1 months, with 65% of patients alive at 12 months. In the near future
more data will be available to judge the true potential of this strategy.
The phase III NRG-BR004 trial (NCT03199885) is going to randomize
480 metastatic HER2+ patients to first-line treatment with pacli-
taxel + trastuzumab + pertuzumab with or without pembrolizumab.
Additionally, in second-line, after trastuzumab therapy, the randomised
phase II KATE2 study (NCT02924883) is going to assess the safety and
efficacy of T-DM1 with or without atezolizumab in 200 patients.
Bispecific antibodies
Bispecific antibodies (BsAb) are monoclonal antibodies that target 2
different epitopes in tandem – either in the same receptor or in different
receptors, opening the possibility for deeper pathway suppression,
multiple pathway suppression or “forced connection” between cancer
cells and immune cells [69]. A growing list of BsAbs are currently being
investigated as treatment options for HER2+ MBC.
MCLA-128 targets both HER2 and HER3, leading to enhanced an-
tibody-dependent cell-mediated cytotoxicity [70]. A Phase I/II study
(NCT02912949) results in 10 heavily pre-treated HER2+ metastatic
patients show a CBR of 70% [71]. Toxicity was mild, consisting of in-
fusion related reactions, diarrhea, rash and fatigue (all grade 1/2). Due
to these encouraging preliminary findings, MCLA-128 is going to be
tested in patients progressing after ≥2 prior anti-HER2 therapies, in-
cluding T-DM1 (NCT03321981 trial).
ZW25 targets two different epitopes on the extracellular domain of
the HER2 receptor [72]. Phase I study (NCT02892123) results in 11
heavily pre-treated 11 BC patients showed an overall DCR of 64%.
Adverse events were diarrhea, infusion reactions and nausea, but all
grade 1/2. An expansion cohort has been opened.
GBR 1302 takes a different approach by targeting both HER2 and
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Cancer Treatment Reviews 67 (2018) 10–20
CD3, redirecting cytotoxic T cells through its CD3 binding arm onto
HER2 expressing cancer cells, with the hope to induce their killing. In
preclinical models, this drug demonstrated potent antitumor effect,
which was dependent on HER2 expression levels [73]. GBR 1302 is
already being tested in progressing HER2+ solid tumours in a phase I
trial (NCT02829372), though no results are available yet.
Antibody-drug conjugates
Antibody-Drug Conjugates (ADCs) combine the specificity of a
monoclonal antibody for a target receptor with the cytotoxicity of a
potent chemotherapy agent [74]. This elegant approach and the early
successes (with T-DM1) of the class have led to a rapidly growing in-
terest in ADCs and to intense clinical development of new molecules.
Two new ADCs are in advanced stages of development in phase III
trials, following good results in phase I/II trials in heavily pre-treated
patients.
SYD-0985, an agent composed by trastuzumab conjugated with
duocarmycin is being tested in an ongoing phase I trial (NCT02277717)
in patients with advanced breast cancer and stomach cancer [75]. A
preliminary report of 38 evaluable breast cancer patients identified 8
PRs in HER2-positive patients. Additionally, 4 patients categorized as
HER2-low (1+ in IHC) presented with PR. Only one dose limiting-event
occurred (pneumonitis) and the agent was overall tolerable. Interest-
ingly, a number of patients presented with ocular complications of mild
nature (dry eyes, increased lacrimation or conjunctivitis) [75].
DS-8201a, a molecule combining an anti-HER2 antibody and an
exatecan derivate, has likewise presented phase I results in advanced
breast cancer (both HER2+ and HER2-low) totalling 130 patients, with
an ORR of 61.4% in HER2+ patients and 31.6% in HER2-low patients.
The HER2+ cohort included, notably, patients pre-treated with both
pertuzumab and T-DM1. Grade 3 or 4 adverse events were remarkably
rare [76,77].
Though the results of these trials are exciting, notably with the
possibility of redefining which patients can be candidates to anti-HER2
therapy [78], and the fact that other promising agents are being tested
(including XMT-1522 and MEDI 4276) it is important to stress that at
least one new ADC – MM302 has failed in the HERMIONE study (ter-
minated by IDMC recommendation) despite encouraging phase I results
[79–82]
 Table 2
Ongoing trials in HER2+ advanced breast cancer.
Drug Trial Phase Population Regimen Sample size
N. Pondé et al.

Designed ankyrin repeat proteins

MP0274 Not Applicable I Refractory advanced HER2+ Breast Cancer MP0274 36

CDK 4/6 inhibitors

Palbociclib NCT01976169 I RB-proficient at least one previous line of anti-HER2 therapy Palbociclib + T-DM1 17
NCT02448420 II 2–4 previous lines of anti-HER2 therapy Palbociclib + Trastuzumab +/− Letrozole 138
NCT02947685 III First line advanced HER2+ Breast Cancer 4–8 Cycles of induction therapy + Trastuzumab + Pertuzumab followed by AI/ 496
Fulvestrant + Pertuzumab + Trastuzumab +/− Palbociclib
NCT03304080 I/II First line advanced HER2+ Breast Cancer Anastrozole + Palbociclib + Trastuzumab + Pertuzumab 36
NCT03054363 I/II Up to 1 previous line of anti-HER2 therapy Tucatinib + Palbociclib + Letrozole 40
Ribociclib NCT02657343 I/II Cohort A: at least one previous line of anti-HER2 treatment; Cohort B: at A: Ribociclib + T-DM1 or B: Ribociclib + Trastuzumab 86
least trastuzumab, pertuzumab and T-DM1
Abemaciclib NCT02675231 II At least 2 lines of anti-+HER2 therapy (including T-DM1) Abemaciclib + Trastuzumab+ Fulvestrant vs Abemaciclib + Trastuzumab vs 225
Trastuzumab + chemotherapy

Anti-PD-1/Anti-PD-L1
Atezolizumab NCT02924883 II At least Previous paclitaxel + trastuzumab T-DM1 + Atezolizumab vs T-DM1 + Placebo 200
NCT03417544 II HER2+ BC with brain metastasis Trastuzumab + Pertuzumab + Atezolizumab 33
NCT02605915 Ib Advanced HER2+ BC Cohort 1A: Atezolizumab + Trastuzumab + Pertuzumab 98
Cohort 1B: Atezolizumab + T-DM1 (3.6 mg/kg)
Cohort 1C : Atezolizumab + T-DM1 (3.0 mg/kg)
Cohort 1C : Atezolizumab + T-DM1 (2.4 mg/kg)
Cohort 1F: Docetaxel + Trastuzumab + Pertuzumab + Atezolizumab

NCT03125928 II 1 line of ET max or adjuvant trastuzumab/pertuzumab if more than 12 m Paclitaxel + Trastuzumab + Pertuzumab + Atezolizumab 50
Pembrolizumab NCT03199885 III 1 line of HT max or adjuvant T/P ≥ 6 m Paclitaxel + Trastuzumab + Pertuzumab vs Paclitaxel + Trastuzumab + 480

15
Pertuzumab + Pembrolizumab
NCT03032107 I At least Previous paclitaxel + trastuzumab Pembrolizumab + T-DM1 27
Durvalumab NCT02649686 I Failed at least 2 lines of anti-HER2 therapy (including Trastuzumab and Durvalumab + Trastuzumab 15
Lapatinib)

New Anti-HER AntiBodies

Margetuximab NCT02492711 III HER2+ MBC with at least 2 previous lines of anti-HER2 therapy Trastuzumab + Chemotherapy vs Margetuximab + chemotherapy 540

Bi-specific antibodies
MCLA-128 NCT02912949 I/II Relapsed refractory HER2+ tumours MCLA-128 130
NCT03321981 II Cohort 1: HER2+ advanced breast cancer Cohort1: MCLA-128 + Trastuzumab or MCLA-128 + Trastuzumab + vinorelbine 120
Cohort 2: ER+/HER2-Low Cohort 2 : MCLA-128 + latest ET received by the patient
GBR 1302 NCT02829372 I Relapsed refractory HER2+ solid tumours GBR 1302 60
ZW25 NCT02892123 I HER2+ solid tumours (including HER2 1+) ZW25 99

Antibody drug conjugates

SYD985 NCT02277717 I Part I: Any refractory tumour; Part II: HER2+ tumours SYD985 160
NCT03262935 III HER2+ metastatic breast cancer at least 2 previous lines of anti-HER2 SYD958 vs Physician’s choice 345
therapy
DS-8201a NCT02564900 I Part 1: Multiple tumour types; Part 1: HER2+ MBC having previously DS-8201a 198
received T-DM1
NCT03368196 I HER2+ Advanced tumours including breast cancer DS-8201a 12
NCT03248492 II HER2+ advanced breast cancer – 10 of which should be patients who could DS-8201a (3 dose levels) 230
not tolerate t-DM1 treatment
XMT-1522 NCT02952729 I MBC (1) HER2+ treated previously with T-DM1; (2) HER2 Low XMT-1522 120
MEDI4276 NCT02576548 I/II HER2+ MBC previously treated with trastuzumab, pertuzumab and T-DM1 MEDI4276 216

Alfa-specific PI3K inhibitors

Taselisib NCT02390427 I HER2+ metastatic breast cancer with any previous anti-HER2 therapy Taselisib + T-DM 1 or Taselib + Trastuzumab-DM1 + Pertuzumab or Taselisib + Trastuzumab 78
+Pertuzumab or Taselisib + Trastuzumab+Pertuzumab + Paclitaxel
(continued on next page)
Cancer Treatment Reviews 67 (2018) 10–20
N. Pondé et al. Cancer Treatment Reviews 67 (2018) 10–20

Sample size New Anti-HER2 antibodies

At least a part of the effect trastuzumab has on HER2-positive breast

480

104

621
152

240
48

50

57

30

70

40

63
48

50
cancer cells derives from antibody dependent cellular toxicity [83].
This immune-mediated cytotoxic effect may vary according to the
“host” FcyR polymorphism for trastuzumab [84]. A new generation of
anti-HER2 antibodies is in development, with margetuximab being the
most advanced. Margetuximab shows increased ability to induce ADCC
regardless of FcyR isoform in vitro through optimized binding [85]. The
latest results of a Phase I trial with 66 patients with HER2+ carci-
nomas, including 27 BC patients (all pre-treated with more than 1 line
Capecitabine + Trastuzumab + Tucatinib vs Cape + Trastuzumab + Placebo

of anti-HER2 therapy) showed positive signs of activity, with 11 pa-

tients experiencing some tumour reduction and 4 (17%) a confirmed
response. Overall number of adverse events was very low with almost
no grade 3/4 events [86]. On the base of this evidence, the SOPHIA trial
(NCT0249271), will compare head to head margetuximab combined
with chemotherapy compared to trastuzumab + chemotherapy in pa-
Neratinib + Capecitabine vs Lapatinib + Capecitabine

Pyrotinib + Capecitabine vs Lapatinib + Capecitabine

tients who received at least 2 lines of anti-HER2 therapy.

New pan-HER TKIs

PanHER tyrosine kinase inhibitors (TKIs) are orally bio-available

Neratinib + Fulvestrant vs Neratinib
Alpelisib + LJM716+Trastuzumab

small molecules that act on the intracellular domains of several HER-

family transmembrane receptors [87]. Lapatinib was the first to be
Capecitabine 7/7 + Neratinib

approved for clinical use, though toxicity proved an issue, and hopes
about its effectiveness in brain metastasis due to blood-brain barrier
penetration were partly dashed [88,89]. A “second generation” of
Tucatinib + T-DM1

Neratinib + T-DM1

panHER inhibitors – neratinib and afatinib also showed a frustratingly

low efficacy with significant toxicity in a number trials in the advanced
Poziotinib

Poziotinib

Poziotinib
Tucatinib

Neratinib

Pyrotinib

setting [90–92]. The ongoing NALA (NCT01808573) trial testing ner-

Regimen

atinib in third line or more combined with capecitabine vs lapa-

tinib + capecitabine may rehabilitate neratinib in the advanced setting
and also provide valuable data on the efficacy of lapatinib in third line
1 or 2 failed previous lines of therapy, trastuzumab should have been used in
HER2+ metastatic breast cancer having received previous Pertuzumab and

HER2+ (or EGFR/AR+) failed at least to lines of therapy including use of

Elderly (60 or older) patients with HER2+ advanced breast cancer having

after pertuzumab/T-DM1 [6]. For neratinib, the development of an

Failed at least 2 lines of anti-HER2 therapy (including Trastuzumab and

Failed at least 2 lines of anti-HER2 therapy (including Trastuzumab and

Have received at least trastuzumab, Pertuzumab and T-DM1 previously

Failed at least 2 lines of anti-HER2 therapy (including T and T-DM1)

adequate regimen of diarrhea control, as is the goal of the CONTROL

Failed at least 2 lines of anti-HER2 therapy (including Trastuzumab,

trial will be invaluable to render its daily use more acceptable to pa-
tients [93].
Phase II: up to 4 previous lines, including capecitabine-based
Must have previously received trastuzumab and pertuzumab

Several new panHER TKIs are in development (Table 2), including

poziotinib, pyrotinib and tucatinib. Both poziotinib and pyrotinib have
recent Phase I/II data suggesting some single agent efficacy but non-
negligible toxicity [57,94]. Pyrotinib was tested in a randomised phase
T-DM1, PIK3CA mutants for dose-escalation

Failed at least 2 lines of anti-HER2 therapy

At least Previous Trastuzumab + Paclitaxel

II trial (N = 128) in combination with capecitabine vs lapatinib + ca-

pecitabine in patients treated with a maximum of 2 previous lines of
Phase I : any number of previous lines

Refractory advanced HER2+ tumours

failed approved anti-HER2 therapies

therapy. Results suggest improved outcomes (ORR 78.5% vs 57.1%,

mPFS 18.1 months vs 7 months) at the cost of heightened toxicity. It is
Lapatinib, Pertuzumab, T-DM1)

important to note that almost half of patients in this trial had not re-
Anthracycline and taxane

ceived any previous line of anti-HER2 therapy. Tucatinib is the most

interesting among the new anti-HER TKIs, as it is selective for HER2
inhibition, which may reduce toxicity, thereby improving dose-in-
tensity and efficacy. Early efficacy data suggests significant benefit,
one of them
Population

Lapatinib)

Lapatinib)

notably in patients with brain metastasis [95]. It is being tested cur-

rently in the HER2CLIMB trial in patients after the second line and
having received both trastuzumab and T-DM1 with or without brain
metastasis [96].
Phase

I/II
I/II
III

III
II

II

II

II

II
II
I

Anti-HER2-mTOR/PI3K inhibitor combinations

NCT02167854

NCT00650572

NCT01983501
NCT02614794

NCT02418689

NCT02544997

NCT02659514
NCT01808573
NCT03289039
NCT02673398

NCT02236000
NCT03377387

NCT03080805

NCT02500199

Acquired resistance to anti-HER2 therapy may arise through many

HER2 tirosine kinase inhibitors

mechanisms, including through PI3K/Akt/mTOR pathway activation

Trial

[97]. Early attempts to inhibit this pathway, including the BOLERO-1

Table 2 (continued)

and BOLERO-3 trials evaluating anti-mTOR-based (everolimus) com-

binations showed, however, disappointing efficacy results and in-
creased toxicity [98]. The discovery of the PI3K inhibitors, however,
Poziotinib
Tucatinib

Neratinib

Pyrotinib
Alpelisib

has led to renewed impetus for this strategy [99].

Drug

The first results in patients with advanced HR+/HER2- tumours

with pan-PI3K inhibitors again proved dashed hopes. The phase III

16
N. Pondé et al.
BELLE-2 and BELLE-3 trials, evaluating the combination of buparlisib
with fulvestrant, showed marginal PFS benefit (except in PIK3CA mu-
tated cases) and exceptional toxicity, including concerning adverse
events like depression, anxiety and three suicide attempts, which could
be related to its high blood–brain barrier penetration [100,101]. The
issue of toxicity has continued to plague panPI3K inhibitors, leading to
the early interruption of the NeoPHOEBE trial after only 50 patients
accrued. In NeoPHOEBE, patients with HER2+ tumours were separated
in two independent cohorts by PIK3CA mutation status and randomised
to receive buparlisib or placebo plus trastuzumab (first 6 weeks) fol-
lowed by buparlisib or placebo with trastuzumab and paclitaxel [102].
Overall, pCR rate was similar between buparlisib and placebo arms
(32% vs. 40%), but with a trend towards higher RR (69% vs. 33%,
p = 0.053) and a significant decrease in Ki67 (75% vs. 27%) in the
buparlisib versus placebo arm in the ER+ subgroup, suggesting a po-
tential role for PI3K inhibition in triple positive tumours.
Most present research efforts have been recently focused on devel-
oping α-specific PI3K inhibitors (such as taselisib and alpelisib) in
PIK3CA mutated tumours, in the hope that increased selectivity will
improve the therapeutic index.
Taselisib, in combination with different anti-HER2 therapies, is
studied in an ongoing phase Ib study (NCT02390427) in patients with
any previous number of anti-HER2 therapies. Alpelisib was combined
with LJM716 (a HER3 inhibitor) and trastuzumab in pertuzumab and T-
DM1 pre-treated metastatic HER2+ patients with a PIK3CA mutation
(NCT02167854). Preliminary results indicated high toxicity (diarrhea,
mucositis, hypokalemia and liver toxicity) and limited activity (best
response was stable disease in 5 of 6 evaluable patients), leading the
authors have proposed to explore alternative dose schedules [103]. The
study is still ongoing and should be completed by June 2018. Another
phase I study (NCT02038010) has combined alpelisib with T-DM1 in
trastuzumab pre-treated HER2+ patients and showed significant ac-
tivity: in 17 heavily pretreated patients (of whom 9 progressed on prior
T-DM1) the median PFS was 6 months and toxicity included rash, hy-
perglycemia and nausea [104]. A phase II study is planned to follow.
Finally, MK-2206 is a pan-Akt inhibitor that was combined in phase
I studies with trastuzumab and with lapatinib in patients with HER2-
positive solid tumours, with an acceptable safety profile and clinical
activity [105,106]. It is now being explored as a single-agent or in
combination with trastuzumab, in conjunction with chemotherapy, in
the neoadjuvant adaptive I-SPY 2 (NCT01042379) trial.
Anti-HER2-CDK 4/6 inhibitor combinations
In vitro studies suggest that cyclin D1/CDK4 may be a critical
pathway permitting resistance of ER+/HER2+ cancer cells to anti-
HER2 therapy and that CDK4/6 inhibitors are active both as single
agents and in combination with trastuzumab [107,108]. This biologic
rationale, coupled with the recent success of this class in advanced ER-
positive disease have led to interest in combining anti-HER2 therapy
and CDK 4/6 inhibitors in “triple positive” patients. The MonarcHER
(NCT02675231) trial is randomising 225 patients treated with at least 2
lines of anti-HER2 treatment between chemotherapy + trastuzumab,
fulvestrant + trastuzumab + abemaciclib or trastuzumab + abemaci-
clib. PATRICIA (NCT02448420), interestingly, includes both ER- and
ER + cohorts of patients treated with 2–4 previous lines of therapy.
ER + patients will receive either trastuzumab + palbociclib or trastu-
zumab + palbociclib + letrozole and ER- patients receive trastu-
zumab + palbociclib. Finally, the PATINA trial (NCT02947685), a
randomised phase III trial, will test dual blockade with trastu-
zumab + pertuzumab with an AI with or without palbociclib after 4–8
cycles of induction chemotherapy + dual blockade.
Anti-HER2-histone deacetylases inhibitor combinations
Gene expression is modulated by modifications of histone proteins.
17
Cancer Treatment Reviews 67 (2018) 10–20
Inhibition of the enzymes that regulate this process, such as the histone
deacetylases (HDACs) negatively impacts cellular proliferation, thus
rendering HDACs a potential therapeutic target [109].
Entinostat is an orally bioavailable HDCA1/3 inhibitor. It has shown
activity in breast cancer in vivo and in vitro models of breast cancer, in
combination with trastuzumab or lapatinib, including in HER2-positive
breast cancer, in which it impacts particularly PI3K/AKT signalling, one
of the more common resistance mechanisms seen in HER2+ BC [109].
This potential has been confirmed in a phase I study of entino-
stat + lapatinib (with or without trastuzumab), with 35 evaluable pa-
tients showing a CBR of 20% in heavily pretreated patients [110]. These
initial results have yet to be followed by a Phase II study.
DARPins
Designed ankyrin repeat proteins (DARPins) offer a novel way to
inhibit HER2 signalling by separating receptor activation from down-
stream signalling pathways, inducing apoptosis, with very high po-
tency, stability and specificity [111]. Each DARPin can be combined to
another in modular fashion, allowing for the development of full mo-
lecules that bind to different domains of the same receptor. MP0274 is
the first molecule targeting HER2 with much greater affinity when
compared to existing antibodies, powerfully inhibiting HER2/HER3
signalling. It binds to two different HER2 epitopes, as well as to albumin
in order to extend its-half life. It has shown activity in preclinical
models (in vitro and in vivo) and is now in Phase I study in refractory
HER2+ advanced breast cancer [112].
Conclusion
The early 2010s witnessed a shake-up of the treatment standards for
HER2+ advanced BC. Despite significant improvement in outcomes,
those years have left a number of open clinical questions which we are
only now starting to answer. “Triple positive” disease deserves to be the
focus of more appropriate trials – and it is likely that CDK 4/6 inhibitors
will prove to be the necessary incentive for private investment and,
therefore progress, in this field. Despite intense, albeit fragmented,
translational research efforts we do not have any validated biomarkers
beyond HER2 itself and patients are largely selected for participation in
trials in the same manner they were in the late 1990’s. Molecular
imaging studies need to be pursued, furthermore, the potential role of
ctDNA plasma monitoring needs to be further investigated in phase III
trials specifically designed to validate it as a strategy for therapy
choice/response assessment. Improvement in patient selection and in
treatment response assessment with the hope to limit unnecessary
toxicity and to improve cost-effectiveness. The next decade will see
numerous drugs combinations come to phase III (and hopefully clinical
practice). Without enhanced collaboration between researchers and
pharmaceutical companies to share biomarker results at a patient level,
no palpable progress will be made towards a clinically valid and useful
predictive biomarker.
Conflicts of interest
Dr. Piccart has received honoraria from AstraZeneca, Lilly, MSD,
Novartis, Odonate, Pfizer, Roche-Genentech, Crescendo Biologics,
Periphagen, Huya, Debiopharm, PharmaMar, G1 Therapeutics,
Menarini, Seattle Genetics, Immunomedics. The institute she directs has
received grants from AstraZeneca, Lilly, MSD, Novartis, Pfizer, Roche-
Genentech, Synthon, Radius, Servier. The remaining authors have no
conflicts of interest to disclose.
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sector.
N. Pondé et al.
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