Macpherson et al.

Breast Cancer Research (2020) 22:1

https://doi.org/10.1186/s13058-019-1178-0

RESEARCH ARTICLE Open Access

A phase I/II study of epertinib plus

trastuzumab with or without chemotherapy
in patients with HER2-positive metastatic
breast cancer
Iain R. Macpherson1, Pavlina Spiliopoulou1, Saeed Rafii2, Matilde Saggese2, Richard D. Baird3,
Javier Garcia-Corbacho3, Antoine Italiano4, Jacques Bonneterre5, Mario Campone6, Nicola Cresti7, John Posner8,
Yousuke Takeda8, Akinori Arimura8 and James Spicer9*

Abstract
Background: Epertinib (S-222611) is a potent reversible inhibitor of HER2, EGFR and HER4. This trial evaluated the
safety, tolerability, pharmacokinetics and antitumour activity of daily oral epertinib combined with trastuzumab (arm
A), with trastuzumab plus vinorelbine (arm B) or with trastuzumab plus capecitabine (arm C), in patients with HER2-
positive metastatic breast cancer (MBC).
Methods: Eligible patients, with or without brain metastases, had received prior HER2-directed therapy. A dose-
escalation phase determined the tolerability of each combination and established a dose for further study. Further,
patients were recruited to expansion cohorts in each of the 3 arms to further explore efficacy and safety.
Results: The recommended doses of epertinib were 600 mg, 200 mg and 400 mg in arms A, B and C, respectively.
The most frequent grade 3/4 adverse event (AE) was diarrhoea in all arms, which was manageable with medical
intervention and dose modification. The objective response rate (complete response [CR] plus partial response [PR])
in heavily pre-treated HER2-positive MBC patients at the recommended doses of epertinib combined with
trastuzumab was 67% (N = 9), with trastuzumab plus vinorelbine was 0% (N = 5) and with trastuzumab plus
capecitabine was 56% (N = 9). Notably, 4 of 6 patients previously treated with T-DM1 responded in the arm A
expansion cohort (epertinib plus trastuzumab). In the arm C expansion cohort (epertinib plus trastuzumab plus
capecitabine), 4 of 7 patients responded despite previous exposure to capecitabine. Measurable regression of brain
metastases was observed in patients with CNS target lesions treated in both arms A and C.
Conclusion: We observed safety, tolerability and encouraging antitumour activity of epertinib combined with
trastuzumab, or with trastuzumab plus capecitabine. This supports further evaluation of these combinations in
patients with pre-treated HER2-positive MBC, with or without brain metastases.
Trial registration: EudraCT Number: 2013-003894-87; registered 09-September-2013.
Keywords: Epertinib, EGFR, HER2, HER2-positive breast cancer, Trastuzumab

* Correspondence: [email protected]
9
School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s
Hospital, 3rd Floor, Bermondsey Wing, St Thomas Street, London SE1 9RT, UK
Full list of author information is available at the end of the article

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
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Macpherson et al. Breast Cancer Research (2020) 22:1 Page 2 of 9

Background anti-HER2 therapy and then progressed. To assess

Overexpression of the human epidermal growth factor expression of HER2, fresh tumour biopsies or archival
receptor 2 (HER2) is found in 15–20% of patients tissue were used, and HER2 status could be confirmed
with breast cancer and denotes an aggressive subtype by either central or local assessment. Other eligibility
of the disease [1–3]. Outcomes have improved sub- criteria included measurable disease as per Response
stantially with the development of trastuzumab and Evaluation Criteria In Solid Tumours (RECIST) v1.1, an
subsequently other anti-HER2 agents including pertu- Eastern Cooperative Oncology Group (ECOG) perform-
zumab, ado-trastuzumab emtansine (T-DM1) and ance status of 0 or 1, and adequate bone marrow, renal,
lapatinib. Metastatic HER2-positive cancer will often hepatic and left ventricular function. Patients who had
respond to sequential lines of HER2-targeted therapy, previously received vinorelbine and/or capecitabine were
indicating an ongoing dependence on HER2 signal- eligible, as were patients with brain metastases. Con-
ling. Hence, current management protocols comprise comitant medication with strong CYP3A4 inhibitors/in-
first-line trastuzumab and pertuzumab with taxane ducers, or with CYP3A4 substrates with a narrow
[4], and second-line T-DM1 [5]. Lapatinib and cape- therapeutic index, was prohibited. This study was
citabine are considered an option in the third-line approved after review by the relevant regulatory and
setting [6]. Given the development of resistance to independent ethics committees (EudraCT Number:
existing drugs, and the ongoing dependence on HER2, 2013-003894-87) and was conducted in accordance with
there is a potential role for additional HER2-targeting the Declaration of Helsinki and International Conference
therapies. Furthermore, there remains an unmet need on Harmonization Good Clinical Practice. All patients
for drugs with greater penetration of the central ner- provided written informed consent before enrolment.
vous system (CNS).
Epertinib (S-222611, Shionogi & Co. Ltd., Osaka, Study design and drug administration
Japan) is an orally active, reversible, selective and po- This phase I/II, multi-centre, open-label study com-
tent inhibitor of the epidermal growth factor receptor prised dose-escalation and expansion components to
(EGFR), HER2 and HER4 receptor tyrosine kinases. evaluate safety, tolerability, PK and preliminary antitu-
Compared with lapatinib, epertinib showed more pro- mour activity of epertinib administered orally once a day
longed inhibition of phosphorylation of EGFR and in combination with trastuzumab (arm A), trastuzumab
HER2 in vitro, and 4–6-fold greater antitumour po- plus vinorelbine (arm B) or trastuzumab plus capecita-
tency in mouse xenograft models [7]. Superior sur- bine (arm C). Epertinib oral dosing started on day 3 of
vival was also observed in a brain metastasis model of cycle 1 (after 48 h PK blood sampling for capecitabine or
breast cancer, with good penetration to CNS tumours vinorelbine) and then administered continuously. The
[7, 8]. A phase I study conducted in patients with protocol-specified duration of study treatment was 36
various solid tumours, driven by EGFR and/or HER2, weeks unless there was radiographically documented dis-
with or without brain metastases, demonstrated that ease progression or dose-limiting or intolerable toxicity.
once-daily dosing of epertinib monotherapy at 800 mg After 36 weeks participants who were benefiting could
was well-tolerated [9, 10]. Promising antitumour ac- continue to receive epertinib via a separate named pa-
tivity was also observed, particularly in HER2-positive tient program.
metastatic breast cancer (MBC), including partial re- In the dose-escalation component, a modified ‘3 + 3’
gression of brain metastases [9, 10]. design was used to assess the safety and tolerability of
In this study, we evaluated the safety, tolerability, each combination. The dose of epertinib was escalated
pharmacokinetics (PK) and efficacy of epertinib in com- from the initial dose (400 mg in arm A and 200 mg in
bination with trastuzumab, or with trastuzumab plus arms B and C) provided at least 3 subjects had com-
chemotherapy (either vinorelbine or capecitabine). We pleted 21 days’ treatment with no dose-limiting toxicity
recruited heavily pre-treated patients with HER2-positive (DLT). If any one of the first 3 subjects experienced
breast cancer, with or without brain metastases, aiming DLT, up to 4 further subjects were enrolled at that dose
to determine the recommended dose of epertinib in each level, with dose escalation proceeding if at least 6 sub-
combination and to select the most promising regimen jects completed 21 days’ treatment with no more than 1
for future clinical studies. DLT. Protocol-specified DLTs included uncomplicated
grade 4 neutropenia for ≥ 7 days or neutropenia of any
Methods duration associated with fever > 38.5 °C, grade 3
Patients thrombocytopenia associated with bleeding requiring
Eligible patients were ≥ 18 years old with histologically platelet transfusion; grade 3 or 4 non-haematologic tox-
and/or cytologically confirmed HER2-positive metastatic icity (except incompletely treated nausea, vomiting, or
breast cancer who had previously been treated with any diarrhoea); persistent grade ≥ 2 diarrhoea or nausea and/
Macpherson et al. Breast Cancer Research (2020) 22:1 Page 3 of 9

or grade > 1 vomiting for 7 or more days despite sup- Table 1 Patient demographics and baseline characteristics
portive care; and a decline in LVEF by ≥ 10% from Arm A Arm B Arm C Overall
(N=21) (N=7) (N=17) (N=45)
baseline.
Epertinib + T Epertinib + T + V Epertinib + T + C
Trastuzumab was given intravenously at 8 mg/kg as an
Sex
initial dose and subsequently 6 mg/kg, or at 600 mg/5
mL fixed dose subcutaneously, once every 3 weeks. Pa- Female 21 (100%) 6 (85.7%) 17 (100%) 44 (97.8%)

tients in arm B additionally received vinorelbine 60 mg/ Male 0 1 (14.3%) 0 1 (2.2%)

m2 orally on days 1 and 8 of a 21-day cycle, and patients Age (years)
in arm C received capecitabine 1000 mg/m2 orally twice Mean 57.6 (38-79) 49.0 (36-57) 56.8 (36-75) 56.0 (36-79)
(range)
daily for 14 days followed by a 7-day rest period (21-day
cycles). Loperamide could be used to treat diarrhoea but ECOG PS at screening

was not used for prophylaxis. Arms were expanded up 0 11 (52.4%) 6 (85.7%) 11 (64.7%) 28 (62.2%)
to a further 9 evaluable patients to obtain confirmatory 1 10 (47.6%) 1 (14.3%) 6 (35.3%) 17 (37.8%)
tolerability and PK data to determine a recommended Number of metastatic sites at screening
dose for future clinical studies. 1-3 7 (33.3%) 4 (57.1%) 5 (29.4%) 16 (35.6%)
All adverse events (AEs) were monitored and coded ≥4 14 (66.7%) 3 (42.9%) 12 (70.6%) 29 (64.4%)
using National Cancer Institute (NCI) Common Termin- Number of prior anti-cancer therapy regimens
ology Criteria for Adverse Events (CTCAE) Version 4.0. 1-3 0 1 (14.3%) 6 (35.3%) 7 (15.6%)
Participants were treated until disease progression,
≥4 21 (100%) 6 (85.7%) 11 (64.7%) 38 (84.4%)
treatment-emergent toxicities or withdrawal of consent.
Prior HER2-targeted therapy
Trastuzumab 21 (100%) 7 (100%) 17 (100%) 45 (100%)
Pharmacokinetic analysis T-DM1 15 (71.4%) 3 (42.9%) 13 (76.5%) 31 (68.9%)
Blood samples were assayed for PK profiles of the con- Lapatinib 10 (47.6%) 2 (28.6%) 7 (41.2%) 19 (42.2%)
comitant anticancer drugs (CADs) on 2 occasions, be- Pertuzumab 3 (14.3%) 2 (28.6%) 4 (23.5%) 9 (20.0%)
fore (Day 1-3) and after (Day 22-24) introduction of
Prior Capecitabine / Vinorelbine
epertinib. Dosing with epertinib commenced orally once
Capecitabine 16 (76.2%) 4 (57.1%) 11 (64.7%) 31 (68.9%)
per day on day 3, after the last blood sample of the first
Vinorelbine 9 (42.9%) 1 (14.3%) 10 (58.8%) 20 (44.4%)
CDA PK profile. PK profiles of the CAD in presence of
Abbreviations: T trastuzumab, V vinorelbine, C capecitabine, ECOG Eastern
epertinib and epertinib (its active de-alkylated and lac- cooperative oncology group, PS performance status
tam metabolites) were obtained when the patient had re-
ceived at least 10 consecutive days of combination
therapy. PK sampling was performed at the following
times during treatment; pre dose, 1, 2, 4, 6, 8, 12, 24 and
Results
48 hours post dose for analysis of vinorelbine, and pre
A total of 45 patients with HER2-positive metastatic
dose, 0.5, 1, 2, 4, 6, 8, and 12 hours post dose for cape-
breast cancer were enrolled between August 2014 and
citabine and its major metabolites (5-fluorouracil and
November 2015 at 8 sites in the UK and France. Patient
alpha-fluoro-beta-alanin). The blood samples on day 22
demographics and baseline characteristics are sum-
and 23 were analysed for PK analysis of epertinib, and
marised in Table 1. Of the 45 patients enrolled, 38 (84%)
its active de-alkylated and lactam metabolites (pre dose,
had received at least 4 lines of prior anti-cancer therapy.
1, 2, 4, 6, 8, 12 and 24 hours post dose).
All 45 patients (100%) had previously received trastuzu-
mab, 31 (69%) had also received T-DM1 and 19 (42%)
Tumour evaluation had received lapatinib. Patient disposition is summarised
Tumour response was assessed by each investigator at in Additional file 1: Figure S1.
6- to 9-week intervals according to RECIST v1.1. Pa-
tients who had at least one additional scan after the Safety and tolerability
baseline or patients who had no additional scan but dis- Adverse events occurring in at least 10% of patients are
continued due to clinical disease progression were con- summarised in Table 2. Overall, the most frequently re-
sidered evaluable for response. The objective response ported AEs were diarrhoea, nausea, increased bilirubin,
rate (ORR), comprising the proportion of patients decreased appetite and vomiting. Diarrhoea was gener-
achieving complete response (CR) or partial response ally managed with drugs such as loperamide and some-
(PR), and clinical benefit rate (CBR; the proportion of times by holding and/or reducing the dose of epertinib.
patients achieving CR, PR or stable disease [SD] ≥ 6 Grade 3 diarrhoea was reported in 16 patients (36%)
months) were summarised. with a median duration of 3 days and maximum
Macpherson et al. Breast Cancer Research (2020) 22:1 Page 4 of 9

Table 2 Treatment-emergent adverse events occurring in ≥ 10% of patients

Grade Arm A (N=21) Arm B (N=7) Arm C (N=17) Overall (N=45)
Epertinib + T Epertinib + T + V Epertinib + T + C
all, n (%) ≥3, n (%) all, n (%) ≥3, n (%) all, n (%) ≥3, n (%) all, n (%) ≥3, n (%)
Gastrointestinal disorders
Diarrhoea 20 (95.2) 8 (38.1) 7 (100) 3(42.9) 16 (94.1) 5 (29.4) 43 (95.6) 16 (35.6)
Nausea 17 (81.0) 1 (4.8) 7 (100) 0 12 (70.6) 0 36 (80.0) 1 (2.2)
Vomiting 7 (33.3) 1 (4.8) 4 (57.1) 1 (14.3) 6 (35.3) 0 17 (37.8) 2 (4.4)
Stomatitis 6 (28.6) 0 0 0 5 (29.4) 0 11 (24.4) 0
Constipation 3 (14.3) 0 2 (28.6) 0 3 (17.6) 0 8 (17.8) 0
Abdominal Pain 4 (19.0) 0 1 (14.3) 0 2 (11.8) 0 7 (15.6) 0
Dyspepsia 1 (4.8) 0 1 (14.3) 0 3 (17.6) 0 5 (11.1) 0
Metabolism and nutrition disorders
Decreased appetite 9 (42.9) 0 2 (28.6) 0 6 (35.3) 1 (5.9) 17 (37.8) 1 (2.2)
Hypokalaemia 4 (19.0) 0 1 (14.3) 1 (14.3) 6 (35.3) 3 (17.6) 11 (24.4) 4 (8.9)
General disorders
Fatigue 5 (23.8) 0 3 (42.9) 1 (14.3) 6 (35.3) 0 14 (31.1) 1 (2.2)
Oedema peripheral 2 (9.5) 0 0 0 4 (23.5) 0 6 (13.3) 0
Pyrexia 2 (9.5) 0 2 (28.6) 0 2 (11.8) 0 6 (13.3) 0
Asthenia 1 (4.8) 0 0 0 4 (23.5) 0 5 (11.1) 0
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome 2 (9.5) 0 0 0 11 (64.7) 1 (5.9) 13 (28.9) 1 (2.2)
Rash 5 (23.8) 0 2 (28.6) 0 4 (23.5) 0 11 (24.4) 0
Pruritus 6 (28.6) 0 0 0 2 (11.8) 0 8 (17.8) 0
Dermatitis acneiform 6 (28.6) 0 0 0 0 0 6 (13.3) 0
Blood system disorders
Anaemia 3 (14.3) 1 (4.8) 0 0 6(35.3) 0 9 (20.0) 1 (2.2)
Neutropenia 1 (4.8) 0 4 (57.1) 4 (57.1) 2(11.8) 1 (5.9) 7 (15.6) 5 (11.1)
Infections and infestations
Paronychia 1 (4.8) 0 2 (28.6) 0 6 (35.3) 0 9 (20.0) 0
Upper respiratory tract infection 3 (14.3) 0 2 (28.6) 0 1 (5.9) 0 6 (13.3) 0
Urinary tract infection 2 (9.5) 0 0 0 4 (23.5) 0 6 (13.3) 0
Respiratory disorders
Dyspnoea 2 (9.5) 1 (4.8) 1 (14.3) 0 5 (29.4) 1 (5.9) 8 (17.8) 2 (4.4)
Epistaxis 3 (14.3) 0 2 (28.6) 0 3 (17.6) 0 8 (17.8) 0
Cough 3 (14.3) 0 1 (14.3) 0 2 (11.8) 0 6 (13.3) 0
Nervous system disorders
Headache 4 (19.0) 0 1 (14.3) 0 2(11.8) 0 7 (15.6) 0
Lethargy 2 (9.5) 0 3 (42.9) 0 1 (5.9) 0 6 (13.3) 0
Musculoskeletal disorder
Muscle spasms 2 (9.5) 0 1 (14.3) 0 2 (11.8) 0 5 (11.1) 0
Eye disorder
Dry eye 1 (4.8) 0 1 (14.3) 0 3 (17.6) 0 5 (11.1) 0
Investigations
Blood bilirubin increased 10 (47.6) 1 (4.8) 2 (28.6) 0 10 (58.8) 3 (17.6) 22 (48.9) 4 (8.9)
ALT increased 3 (14.3) 0 5 (71.4) 0 2 (11.8) 1 (5.9) 10 (22.2) 1 (2.2)
Macpherson et al. Breast Cancer Research (2020) 22:1 Page 5 of 9

Table 2 Treatment-emergent adverse events occurring in ≥ 10% of patients (Continued)

Grade Arm A (N=21) Arm B (N=7) Arm C (N=17) Overall (N=45)
Epertinib + T Epertinib + T + V Epertinib + T + C
all, n (%) ≥3, n (%) all, n (%) ≥3, n (%) all, n (%) ≥3, n (%) all, n (%) ≥3, n (%)
AST increased 2 (9.5) 0 3 (42.9) 0 4 (23.5) 1 (5.9) 9 (20.0) 1 (2.2)
Weight decreased 2 (9.5) 0 0 0 3 (17.6) 0 5 (11.1) 0
Abbreviations: T trastuzumab, V vinorelbine, C capecitabine

duration of 8 days per event. Nausea and vomiting were the recommended dose. Two of 9 patients in the 400-
generally low grade. Blood bilirubin elevation, previously mg cohort required dose reduction of epertinib because
reported with epertinib [9, 10], was not associated with of AEs, but no permanent discontinuation was required.
elevation of liver enzymes or haematological abnormal- No grade 5 toxicity was observed across all arms.
ities, except for one patient who experienced liver dys-
function which was subsequently shown to be due to Pharmacokinetic analysis
progression of hepatic metastases. Neutropenia was ob- No relevant differences between treatment arms, or in
served in arm B (57%). The incidence of palmar-plantar the presence and absence of concomitant drugs, were
erythrodysaesthesia was greatest in arm C (65%). found in PK parameters for epertinib and its metabolites
In arm A, grade 3 diarrhoea during the first 21-day (Additional file 3: Table S1). Similarly, the presence of
period of daily dosing with epertinib was observed in 4 epertinib appeared to have no significant effect on the
of 7 patients at the 800-mg dose level. Although only 1 PK of vinorelbine and capecitabine (Additional file 3:
formal DLT was observed, this dose was not considered Tables S2-S4). PK analysis was not performed in the
to be well-tolerated, and therefore, 600 mg was the dose 400-mg cohort in arm B due to temporary drug discon-
recommended for further study of this combination with tinuation for safety purposes during cycle 1.
trastuzumab. Four of 9 patients in the 600 mg cohort
had a dose reduction because of AEs, but no patients Antitumour activity
permanently discontinued treatment because of toxicity. Forty-four of the 45 patients enrolled were evaluable for
In arm B, 200 mg was determined as the maximum tol- tumour response. One patient discontinued without any
erable dose (MTD) because 2 patients in the 400-mg co- efficacy evaluation due to DLT at 800 mg in arm A. The
hort experienced DLTs (grade 4 neutropenia > 7 days, tumour response for each arm and dose are summarised
N = 2). No patient in the 200-mg cohort discontinued in Table 3. The magnitude of response and duration of
treatment because of AEs. In arm C, 600 mg was not treatment for patients receiving epertinib at the clinically
considered to be well-tolerated because withdrawal of recommended dose or MTD in arms A, B and C are
the study drug due to grade 3 diarrhoea lasting less than summarised in Fig. 1 a and b.
7 days (N = 1), or blood bilirubin elevation (N = 1), was In arm A, the ORR at 600 mg epertinib was 67% (6/9
required in 2 of the 4 patients during cycle 1. Although patients). Notably, 4 of 6 patients pre-treated with T-
these were not pre-defined DLTs, 400 mg was defined as DM1, and 5 of 7 patients pre-treated with capecitabine,

Table 3 Antitumour activity in evaluable patients

Dose of epertinib Arm A Arm B Arm C
Epertinib + T Epertinib + T + V Epertinib + T + C
400mg 600mg 800mg 200mg 400mg 200mg 400mg 600mg Overall
N=5 N=9 N=7 N=5 N=2 N=4 N=9 N=4 N=45
BOR
CR 0 0 0 0 0 0 0 0 0
PR 0 6 (66.7%) 1 (14.3%) 0 2 (100%) 0 5 (55.6%) 2 (50.0%) 16 (35.6%)
SD ≥ 6 months 2 (40.0%) 0 1 (14.3%) 4 (80.0%) 0 1 (25.0%) 0 1 (25.0%) 9 (20.0%)
CBR 2 (40.0%) 6 (66.7%) 2 (28.6%) 4 (80.0%) 2 (100%) 1 (25.0%) 5 (55.6%) 3 (75.0%) 25 (55.6%)
PD 2 (40.0%) 1 (11.1%) 2 (28.6%) 0 0 1 (25.0%) 1 (11.1%) 1 (25.0%) 8 (17.8%)
Clinical benefit is defined as objective response plus SD at 6 months
Abbreviations: T trastuzumab, V vinorelbine, C capecitabine, BOR best overall response, CR complete response, PR partial response, SD stable disease, CBR clinical
benefit rate, PD progressive disease
Macpherson et al. Breast Cancer Research (2020) 22:1 Page 6 of 9

Fig. 1 Antitumour activity (a) and duration on treatment (b) for patients in the recommended dose cohorts for each arm. Partial regression of
brain metastases in a 53-year-old patient after 59 days of treatment with epertinib 400 mg in combination with trastuzumab plus capecitabine in
arm C (c). Brain metastases first appeared during prior treatment with trastuzumab with capecitabine, and the patient underwent whole-brain
radiotherapy followed by T-DM1. After further progression in the brain the patient was enrolled in this study. T: trastuzumab, L: lapatinib, K: T-
DM1, P: pertuzumab, V: vinorelbine, C: capecitabine, BM: brain metastases

experienced PR in this cohort. Two of 3 patients with given concerns that there may be insufficient exposure to
brain metastases achieved PR as assessed by RECIST v1.1 epertinib at this dose, no additional patients were enrolled.
in this cohort. In arm B, since there was no tumour re- However, the clinical benefit rate was 80%. In arm C, the
sponse in the first 5 patients treated with 200 mg and, ORR at 400 mg was 56% (5/9 patients). Interestingly, 4 of
Macpherson et al. Breast Cancer Research (2020) 22:1 Page 7 of 9

7 patients previously treated with capecitabine experi- positive MBC [12, 14]. The PHEREXA study has demon-
enced PR in this cohort. One of two patients with brain strated that the addition of pertuzumab to trastuzumab
metastases showed partial regression of CNS lesions as plus capecitabine did not significantly improve PFS [15];
assessed by RECIST v1.1 (Fig. 1c). Across cohorts, a re- objective response rates were 33% with trastuzumab plus
duction in the longest diameter was observed in 4 of 5 pa- capecitabine, and 41% with pertuzumab and trastuzu-
tients with CNS target lesions (Additional file 2: Figure mab plus capecitabine. Although we cannot draw direct
S2). This included all patients treated in the recom- comparisons, in our study the objective response rate
mended dose cohorts (arm A; N = 2 and arm C; N = 2). with epertinib 400 mg in combination with trastuzumab
plus capecitabine was 56%, despite prior capecitabine
Discussion treatment in 7 of 9 patients, supporting further investi-
In combination with trastuzumab, 600 mg daily of epertinib gation of this regimen.
was defined as the recommended dose based on the safety Capecitabine plus lapatinib has been approved in
data. The most frequently occurring AE in this cohort was HER2-positive MBC previously treated with trastuzumab
diarrhoea, which could be managed by anti-diarrhoeal medi- and is often favoured for patients with brain metastases
cation and/or dose reduction. At this dose, epertinib plus [16]. Combining chemotherapy with HER2-directed
trastuzumab showed a remarkable response rate (67%) in pa- therapy for the management CNS disease is further sup-
tients heavily treated with regimens including trastuzumab, ported by the activity of capecitabine plus neratinib in
T-DM1, lapatinib, pertuzumab and chemotherapy. This may patients with treatment-refractory brain metastases
indicate greater efficacy for dual therapy with trastuzumab, treated within the TBCRC 022 study [17]. The CNS re-
given the 19% response rate that was observed with epertinib sponse rate of 49% compared favourably to the 8% re-
monotherapy at a higher dose of 800 mg in HER2-positive sponse rate that was previously reported for a TBCRC
MBC [10]. Additional benefit for combination with trastuzu- 022 neratinib monotherapy cohort [18]. In our study,
mab over single agent epertinib, despite previous disease prolonged disease stabilisation (≥ 6 months) was seen in
progression on a trastuzumab-containing regimen, would be 2 of 3 patients with brain metastases in arm A, and a
consistent with observations with other HER2-directed partial response in brain metastases occurred in one of 2
tyrosine kinase inhibitors. For example, the combination of patients in arm C. All patients had received prior radio-
lapatinib plus trastuzumab was superior to lapatinib therapy and experienced subsequent CNS progression.
monotherapy in HER2-positive MBC that had progressed on We have recently reported that both epertinib and lapa-
trastuzumab in terms of median progression-free survival tinib accumulate to a comparable extent in tumour de-
(PFS), although not response rate [11]. posits of a rapidly growing mouse brain metastasis
In clinical practice, trastuzumab is often continued be- model. By contrast, only epertinib accumulates in brain
yond progression with a switch to an alternative combin- metastases derived from a slow-growing tumour cell
ation chemotherapy agent, as this improves outcomes line, in which the blood-tumour barrier can be consid-
compared with chemotherapy alone [12]. Standard first- ered to be intact [8]. These pre-clinical observations,
line therapy in MBC is trastuzumab plus taxane with or combined with our clinical findings, suggest that eperti-
without pertuzumab, and the chemotherapy regimens nib may be particularly effective in preventing or con-
tested with epertinib and trastuzumab in this trial where trolling brain metastases in patients.
chosen with this standard of care in mind. In combination
with trastuzumab plus vinorelbine, 200 mg of epertinib Conclusions
was defined as MTD because of grade 4 neutropenia [13]. Combination therapy of epertinib with trastuzumab
There was no pharmacological interaction between eperti- showed robust antitumour activity with manageable
nib 200 mg and vinorelbine based on plasma exposure, al- diarrhoea even in heavily pre-treated patients. Epertinib
though a PK analysis could not be completed in the two in addition to trastuzumab, with or without capecitabine,
patients treated in the 400 mg cohort because of drug ces- could be an effective regimen to treat refractory HER2-
sation related to the DLTs. Since neutropenia has not positive breast cancer, including those patients with
been reported in patients receiving monotherapy with CNS metastases, and merits further clinical evaluation.
epertinib [9, 10], or observed in arms A or C our study, it
is likely that it was attributable to the vinorelbine in arm
Additional files
B. At an epertinib dose of 200 mg in combination with
trastuzumab plus vinorelbine, there were no tumour re- Additional file 1: Figure S1. Patient disposition. (TIFF 7122 kb)
sponses in the first 5 patients and so recruitment to this Additional file 2: Figure S2. Waterfall plot of maximum relative brain
arm was halted. tumour reduction (as per RECISTv1.1) in comparison to baseline in all
Trastuzumab plus capecitabine combination therapy is patients with CNS target lesions (N = 5). One column represents one
patient. (TIFF 7122 kb)
considered to be effective in heavily pre-treated HER2-
Macpherson et al. Breast Cancer Research (2020) 22:1 Page 8 of 9

Additional file 3: Table S1. Summary of Geometric Mean (Geometric Competing interests
CV%) Pharmacokinetics Parameters for Epertinib and its Metabolites with JP undertakes consultancy for and JS has received honoraria from Shionogi
concomitant anticancer drugs (CADs). Table S2. Summary of Geometric Mean & Co., Ltd. Japan. RB undertakes consultancy for and has received travel
(Geometric CV%) Pharmacokinetics Parameters for Vinorelbine with and expense reimbursement from Shionogi Limited UK. SR has received travel
without Epertinib (Arm B). Table S3. Summary of Geometric Mean (Geometric expense reimbursement from Shionogi Limited UK. MS is now an employee
CV%) Pharmacokinetics Parameters for Capecitabine with and without of AstraZeneca. YT and AA are employees of Shionogi & Co., Ltd. IM has
Epertinib (Arm C). Table S4. Summary of Geometric Mean (Geometric CV%) received honoraria and travel expenses from Roche Products UK Ltd. All
Pharmacokinetics Parameters for 5-Fluorouracil following treatment with Cape- remaining authors declare that they have no competing interests.
citabine with and without Epertinib (Arm C) (DOCX 52 kb)
Author details
1
Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. 2Sarah
Abbreviations Cannon Research Institute UK, London, UK. 3Cancer Research UK Cambridge
AE: Adverse event; ALT: Alanine aminotransferase; AST: Aspartate Centre, Cambridge, UK. 4Institut Bergonie, Bordeaux, France. 5Centre Oscar
aminotransferase; BOR: Best overall response; CAD: Concomitant anti-cancer Lambret, Lille, France. 6Institut de cancérologie de l’Ouest Site René
drug; CBR: Clinical benefit rate; CNS: Central nervous system; CR: Complete Gauducheau, Saint Herblain, France. 7Newcastle upon Tyne and Sir Bobby
response; CTCAE: Common Terminology Criteria for Adverse Events; Robson Cancer Trials Research Centre, Freeman Hospital, Newcastle
DLT: Dose-limiting toxicity; ECOG PS: Eastern Cooperative Oncology Group University, Newcastle Upon Tyne, UK. 8Shionogi & Co. Ltd., Osaka, Japan.
9
performance status; EGFR: Epidermal growth factor receptor; HER2: Human School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s
epidermal growth factor receptor 2; LVEF: Left ventricular ejection fraction; Hospital, 3rd Floor, Bermondsey Wing, St Thomas Street, London SE1 9RT,
MBC: Metastatic breast cancer; MTD: Maximum tolerable dose; NCI: National UK.
Cancer Institute; ORR: Objective response rate; PD: Progressive disease;
PFS: Progression-free survival; PK: Pharmacokinetics; PR: Partial response; Received: 29 January 2019 Accepted: 26 July 2019
RECIST: Response Evaluation Criteria In Solid Tumours; SAE: Serious adverse
event; SD: Stable disease

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