FULL PAPER

British Journal of Cancer (2014) 110, 1163–1168 | doi: 10.1038/bjc.2014.18

Keywords: trastuzumab; S-1; cisplatin; HERBIS

Phase II study of trastuzumab in combination
with S-1 plus cisplatin in HER2-positive
gastric cancer (HERBIS-1)
Y Kurokawa*,1, N Sugimoto2, H Miwa3, M Tsuda4, S Nishina5, H Okuda6, H Imamura7, M Gamoh8, D Sakai9,
T Shimokawa10, Y Komatsu11, Y Doki1, T Tsujinaka12 and H Furukawa13
1

Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, 2-2-E2, Yamadaoka, Suita 565-0871,
Japan; 2Department of Clinical Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, 3-3-1, Nakamichi,
Osaka 537-8511, Japan; 3Department of Upper Gastroenterology, Hyogo College of Medicine, 1-1, Mukogawa-cho, Nishinomiya
663-8501, Japan; 4Department of Gastroenterological Oncology, Hyogo Cancer Center, 13-70, Kitaoji-cho, Akashi 673-8558,
Japan; 5Department of Medical Oncology, Kinki University Faculty of Medicine, 377-2, Ohnohigashi, Osakasayama 589-8511,
Japan; 6Deparment of Medical Oncology, Keiyukai Sapporo Hospital, 1-1-14, Hondori, Sapporo 003-0027, Japan; 7Deparment ofSurgery, Sakai Municipal Hospital, 1-1-1, Yasui-cho, Sakai 590-0064, Japan; 8Deparment of Medical Oncology, Osaki Citizen
Hospital, 2-3-10, Furukawasenjujicho, Osaki 989-6183, Japan; 9Deparment of Frontier Science for Cancer and Chemotherapy,
Osaka University Graduate School of Medicine, 2-2, Yamadaoka, Osaka 565-0871, Japan; 10Graduate School of Medicine andEngineering, University of Yamanashi, 4-4-37, Takeda, Kofu 400-8510, Japan; 11Deparment of Cancer Center, Hokkaido University
Hospital, North 15, West 7, Kita-ku, Sapporo 060-8638, Japan; 12Deparment of Surgery, Kaizuka City Hospital, 3-10-20,
Hori, Kaizuka 597-0015, Japan and 13Deparment of Surgery, Kinki University Faculty of Medicine, 377-2, Ohnohigashi,
Osakasayama 589-8511, Japan
Background: S-1, an oral fluoropyrimidine, plus cisplatin (SP) is a standard regimen for advanced gastric cancer (AGC) in East Asia.
To date, no studies have evaluated the efficacy and safety of trastuzumab combined with SP in patients with human epidermal
growth factor receptor type 2 (HER2)-positive AGC.
Methods: Patients with HER2-positive AGC received S-1 (80–120 mg per day) orally on days 1–14, cisplatin (60 mg m  2)
intravenously on day 1, and trastuzumab (course 1, 8 mg kg  1; course 2 onward, 6 mg kg  1) intravenously on day 1 of a 21-day
cycle. The primary end point was response rate (RR); secondary end points included overall survival (OS), progression-free survival(PFS), time to treatment failure (TTF), and adverse events.
Results: A total of 56 patients were enrolled. In the full analysis set of 53 patients, the confirmed RR was 68% (95% confidence
interval (CI) ¼ 54–80%), and the disease control rate was 94% (95% CI ¼ 84–99%). Median OS, PFS, and TTF were estimated as
16.0, 7.8, and 5.7 months, respectively. Major grade 3 or 4 adverse events included neutropaenia (36%), anorexia (23%), andanaemia (15%).
Conclusions: Trastuzumab in combination with SP showed promising antitumour activity and manageable toxic effects in patientswith HER2-positive AGC.

*Correspondence: Dr Y Kurokawa; E-mail: ykurokawa@gesurg.med.osaka-u.ac.jp
Received 27 September 2013; revised 4 December 2013; accepted 2 January 2014; published online 28 January 2014
& 2014 Cancer Research UK. All rights reserved 0007 – 0920/14

www.bjcancer.com | DOI:10.1038/bjc.2014.18

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Gastric cancer is the second leading cause of cancer deaths
worldwide (Ferlay et al, 2010). A global standard regimen for totreat advanced gastric cancer (AGC) has not been established(Macdonald et al, 2001; Cunningham et al, 2008). In Westerncountries, regimens containing a fluoropyrimidine (fluorouracil
or an oral preparation) plus a platinum compound, and usually
including docetaxel or epirubicin, have been most widely used. In
East Asia, including Japan and Korea, a fluoropyrimidine plus a
platinum compound has been used as standard therapy (Koizumi
et al, 2008; Kang et al, 2009).
Recent studies have shed new light on the molecular mechanisms underlying the development and progression of gastriccancer. Trastuzumab is a monoclonal antibody targeting humanepidermal growth factor receptor type 2 (HER2) with two antigenspecific sites that bind to the juxtamembrane portion of theextracellular domain of the HER2 receptor, thereby preventing
activation of its intracellular tyrosine kinase (Hudis, 2007). The
Trastuzumab for Gastric Cancer (ToGA) study, an international
phase III trial comparing chemotherapy consisting of cisplatin plus
capecitabine or fluorouracil vs trastuzumab plus chemotherapy inpatients with HER2-positive AGC, demonstrated a survival
benefit with the addition of trastuzumab (Bang et al, 2010).
Currently, both the US Food and Drug Administration and theEuropean Medicines Agency approved trastuzumab for thetreatment of patients with HER2-positive AGC, and trastuzumabin combination with cisplatin plus capecitabine or fluorouracil is astandard treatment for HER2-positive AGC in the West.
S-1 is a fluoropyrimidine preparation combining tegafur, aprodrug of 5-fluorouracil (5-FU), gimeracil, and oteracil potassiumin a molar ratio of 1 : 0.4 : 1. Gimeracil is a dihydropyrimidine
dehydrogenase inhibitor, allowing high concentrations of 5-FU to
be maintained (Shirasaka et al, 1996; Diasio, 1999). Two phase II
studies (Sakata et al, 1998; Koizumi et al, 2000) in patients with
AGC showed response rates (RRs) exceeding 40%. The S-1 Plus
cisplatin versus S-1 In RCT In the treatment for Stomach cancer(SPIRITS) phase III trial established S-1 plus cisplatin (SP) as astandard first-line regimen for AGC in the East (Koizumi et al,2008; Japanese Gastric Cancer Association, 2011). However, SPplus trastuzumab has not been evaluated in patients with
HER2-positive AGC to date. We therefore conducted this phase
II study to evaluate the efficacy and safety of SP plus trastuzumab
in HER2-positive AGC.

PATIENTS AND METHODSPatients. We enrolled patients with histologically proven unresectable or recurrent HER2-positive tumours in the stomach or
gastroesophageal junction. Human epidermal growth factor
receptor type 2 status of tumours was evaluated using immunohistochemistry (IHC) and fluorescence in situ hybridisation(FISH). In the IHC testing, HER2 tumour cell-membrane
immunostaining was scored using a four-grade scale (0/1 þ /2 þ
/3 þ ) according to scoring scheme (ToGA score): 0, no staining or
membranous reactivity in o10% of tumour cells; 1 þ , weak, barely
perceptible membranous reactivity in 410% of tumour cells; 2 þ ,complete or basolateral membranous reactivity either nonuniform
or weak in X10% of cells; and 3 þ , complete or basolateral
membranous reactivity of strong intensity in X10% of tumour
cells (Hofmann et al, 2008; Bang et al, 2010). FISH analyses for
HER2 status were carried out according to the manufacturer’s
procedure. The total numbers of HER2 and chromosome 17
signals were counted in at least 20 tumour cell nuclei in two
different areas. The case with HER2/chromosome 17 ratio of X2.0
was defined as FISH positive. In this study, only patients with IHC
3 þ , or IHC 2 þ and FISH positive were eligible. Patients
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Trastuzumab/S-1/CDDP in gastric cancer

were required to have measurable lesions according to the
Response Evaluation Criteria in Solid Tumors (RECIST), version
1.1 (Eisenhauer et al, 2009). Eligibility criteria also included: age
between 20 and 75 years; Eastern Cooperative Oncology Group
performance status score of 0 or 1; leukocyte count between 3500
and 12 000 mm  3, neutrophil count X2000 mm  3, hemoglobin
X9.0 g dl  1, platelet count X100 000 mm  3, serum bilirubino1.5 mg dl  1, creatinine clearance X60 ml min  1 calculatedusing the Cockcroft–Gault formula, serum creatinine
p1.2 mg dl  1, serum aspartate aminotransferase and alanine
aminotransferase o100 IU l  1; and baseline left ventricularejection fraction X50%. Patients were excluded from the study ifthey could not maintain sufficient oral intake, have massive ascites
or pleural effusions, or had received prior chemotherapy orradiotherapy within 6 months before enrollment. The study
protocol was approved by the Osaka Gastrointestinal Cancer
Chemotherapy Study Group (OGSG) Steering Committee andthe institutional review boards of all participating hospitals. All
patients provided written informed consent before enrollment.
This study was registered with UMIN-CTR, UMIN000005739.
Treatment. Trastuzumab was commercially obtained in thisstudy. Patients received cisplatin (60 mg m  2) plus trastuzumab(course 1, 8 mg kg  1; course 2 onward, 6 mg kg  1) intravenously
on day 1 and oral S-1 twice daily at a dose based on body surface
area (o1.25 m2, 40 mg; X1.25 to o1.5 m2, 50 mg; X1.5 m2,
60 mg) on days 1–14 of a 21-day cycle.
This schedule was repeated until disease progression,development of unacceptable toxicity, or patient withdrawal ofconsent. If patients had a neutrophil count less than 1000 mm  3,
platelet count less than 75  103 mm  3, serum creatinine morethan 1.2 mg dl  1, infection with fever, or anorexia, diarrhoea, oral
mucositis, or rash of grade 2 or higher, treatment with S-1 wassuspended. In patients with febrile neutropaenia, grade 4
neutropaenia, grade 3–4 thrombocytopaenia, serum creatinine
41.2 mg dl  1, or grade 3–4 diarrhoea, oral mucositis, or rash,doses of S-1 and cisplatin were reduced starting from the next
cycle. In patients who had grade 3–4 vomiting or anorexia becauseof cisplatin, the dose of cisplatin was reduced. If heart failure or
severe infusion reactions occurred, treatment with trastuzumab
was discontinued.
Evaluations. The primary end point was RR. The secondary end
points were overall survival (OS), progression-free survival (PFS),
time to treatment failure (TTF), and adverse events. Tumours wereassessed every 6 weeks until disease progression, and objective
responses were evaluated according to the RECIST guidelines(version 1.1). For complete response (CR) or partial response (PR),confirmation 4 weeks after initial evaluation was necessary.
An independent review committee assessed responses in all
patients. OS was defined as the time from the date of enrollment
to the date of death from any cause. PFS was defined as the timefrom the date of enrollment to the date of disease progression ordeath from any cause. TTF was defined as the time from the date ofenrollment to the date when the treating physician decided to
discontinue treatment for any reason. Physical examination andblood test were mandatory before each course, and left ventricularejection fraction was assessed every 3 month during treatment.
Adverse events were evaluated according to the National Cancer
Institute Common Terminology Criteria for Adverse Events,
version 4.0.
Statistical analysis. The required sample size was estimated basedon a threshold RR of 35% and an expected RR of 50%, 80% power,
and an alpha value of 0.1 (one-sided) using the binomial test.
Given 2% of ineligible patients, the target sample size wasdetermined to be at least 50 patients. Efficacy was evaluated in
all patients who received at least one dose of the study treatment.
www.bjcancer.com | DOI:10.1038/bjc.2014.18

Trastuzumab/S-1/CDDP in gastric cancer

BRITISH JOURNAL OF CANCER

We used the Kaplan–Meier method to estimate survival curves andGreenwood’s formula to calculate 95% confidence intervals (CIs)for survival rates. Statistical analyses were conducted with R,
version 3.0.1.

RESULTS

Patient background. Between July 2011 and May 2012, a total of
56 patients were enrolled from 29 hospitals in Japan. Two patientswere ineligible because of inadequate renal function or the absenceof measurable lesions. The characteristics of the 54 eligible patientsare listed in Table 1. The median age was 66 years (range ¼ 34–75
years). Two-thirds of patients had differentiated adenocarcinoma.
Only three patients (6%) had recurrent disease; the others hadunresectable lesions. The most frequent sites of metastasis were thelymph nodes (81%), followed by the liver (59%). The proportionsof IHC 3 þ and IHC 2 þ /FISH-positive tumours were 83% and17%, respectively.

Table 1. Eligible patient characteristics

Characteristic

n ¼ 54Age, years
Median
Range

66
34–75

Sex
Male
Female42 (78%)12 (22%)

Performance status01

42 (78%)12 (22%)

Histological type
DifferentiatedUndifferentiated36 (67%)18 (33%)

Previous gastrectomyNoYes

45 (83%)9 (17%)

Unresectable/recurrent
Unresectable
Recurrent with adjuvant chemotherapy
Recurrent without adjuvant chemotherapy

51 (94%)2 (4%)
1 (2%)

Efficacy. Of the 54 eligible patients, 1 patient did not receive anytreatment per protocol because of a decrease in serum hemoglobin
levels after study enrollment. Efficacy and safety analyses were
therefore conducted in the full analysis set of the remaining 53
patients.
The median number of cycles was 6 (range ¼ 1–27), and the
median relative dose intensity for S-1, cisplatin, and trastuzumab
was 76%, 83%, and 96%, respectively. At the time of analysis(August 2013), 51 patients had discontinued treatment. The main
reason for discontinuation was progressive disease (31 patients),
followed by adverse events (16 patients). Four patients underwent
surgery because of a prominent response.
The confirmed RR based on RECIST (version 1.1) was 68%(95% CI ¼ 54–80%; 80% CI ¼ 58–76%; Table 2), so the null
hypothesis for the primary end point (RR p35%) was rejected(Po0.001). The confirmed RRs in the differentiated type cases(n ¼ 35) and the undifferentiated type cases (n ¼ 18) were 69%(95% CI ¼ 51–83%) and 67% (95% CI ¼ 41–87%), respectively.
Among 36 patients with CR or PR, the median time to responseand duration of response were 41 days (range ¼ 33–91 days) and
208 days (range ¼ 42–630 days), respectively. The disease control
rate, that is, the proportion of patients who had a CR, PR, or stabledisease, was 94% (95% CI ¼ 84–99%). Two patients (4%) had a CR.
A waterfall plot of the confirmed best overall response for eachpatient is shown in Figure 1.
The median duration of follow-up at the time of analysis(August 2013) for the 53 patients was 13.5 months. The median OS
was 16.0 months (95% CI ¼ 13.3–not applicable), and the 1-year
OS rate was 67.9% (95% CI ¼ 56.5–81.7%; Figure 2). The median
PFS was 7.8 months (95% CI ¼ 6.0–8.8 months), and the 1-year
PFS rate was 17.0% (95% CI ¼ 9.4–30.8%; Figure 2). The median
TTF was 5.7 months (95% CI ¼ 4.2–7.1 months), and the 1-year
TTF rate was 5.1% (95% CI ¼ 1.4–18.6%).
Safety. All adverse events that occurred in three or more patientsare shown in Table 3. Among the haematological adverse events,
the proportions of grade 3–4 neutropaenia and anaemia were 36%
and 15%, respectively. The most frequent common non-haematological toxicity was anorexia (any grade, 79%; grade 3–4, 23%).
Except for anorexia, there were no grade 3 or 4 toxicities that
occurred in more than 10% of patients. Creatinine was elevated in
24 of 53 patients (45%). Grade 2 infusion-related reactions
occurred in three patients (6%). Heart failure did not occur inany patients.
There was one treatment-related death attributable to myelosuppression. This patient was judged as an ineligible caseafterwards, because creatinine clearance before enrollment was
47.4 ml min  1. Furthermore, S-1 administration continued despitea serum creatinine level of 2.31 mg dl  1 on day 7. Renal
dysfunction led to myelosuppression that progressed to death.
Upon review of the patient’s records, the data and safety

Metastatic sitesa
Lymph nodes
Liver
Lung
Peritoneum
Bone
Other

44 (81%)32 (59%)5 (9%)
5 (9%)
2 (4%)
1 (2%)HER2 status
IHC 3 þIHC 2 þ /FISH positive

45 (83%)9 (17%)

Abbreviations: FISH ¼ fluorescence in situ hybridization; HER2 ¼ human epidermal growth
factor receptor type 2; IHC ¼ immunohistochemistry.
aSome patients had multiple metastatic sites.

www.bjcancer.com | DOI:10.1038/bjc.2014.18

Table 2. Objective response with confirmation based on RECIST

Total

n ¼ 53Complete response

2 (4%)

Partial response

34 (64%)

Stable disease

14 (26%)

Progressive disease

3 (6%)

Response rate (95% confidence interval)

68% (54–80%)

Disease control rate (95% confidence interval)

94% (84–99%)

Abbreviation: RECIST ¼ Response Evaluation Criteria in Solid Tumor.

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Trastuzumab/S-1/CDDP in gastric cancer

CR,

PR

SD,

PD

Increase

100
90
80
70
60
50
40
30
20
10
0
–10
–20
–30
–40
–50
–60
–70
–80
–90
–100

Decrease

Reduction response rate (%)

BRITISH JOURNAL OF CANCER

Figure 1. Waterfall plot of confirmed best overall response.

DISCUSSION

1.0
0.9

Overall survival

0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0

3

6

9

12

15

18

21

24

15

18

21

24

Months1.0

Progression-free survival

0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0

3

6

9

12
MonthsFigure 2. (A) The Kaplan–Meier overall survival and (B) progressionfree survival.

monitoring committee determined that the patient died fromcritical deviations from the eligibility criteria and treatment
protocol.
1166

This multicenter phase II study is the first clinical trial reporting
the efficacy and safety of SP plus trastuzumab in patients with
HER2-positive AGC. We obtained a much higher RR (68%) than
expected. The toxicity profile of our regimen was tolerable, and theincidence of grade 3–4 adverse events were similar to those of
the SP regimen in the SPIRITS study (Koizumi et al, 2008). These
results suggest that SP plus trastuzumab is a potential newtreatment option for patients with HER2-positive AGC.
The ToGA study demonstrated that trastuzumab in combination with cisplatin plus capecitabine or fluorouracil was superior tocisplatin plus capecitabine or fluorouracil alone (Bang et al, 2010).
The RR was 35% in the chemotherapy group and 47% in the
trastuzumab plus chemotherapy group. In the aforementioned
phase II study of a 3-week cycle of SP, the RR was 48%, comparedwith 68% in the present study, suggesting that trastuzumab
considerably enhanced the effectiveness of chemotherapy, which isconsistent with the results of the ToGA study. In addition, themedian OS and PFS in our study were 16.0 and 7.8 months,
respectively, whereas the subgroup of Japanese patients in the
trastuzumab arm of the ToGA study had a median OS and PFS of
15.9 and 6.2 months, respectively (Sawaki et al, 2012). Althoughthese results must be interpreted with caution because of thedifferences between the ToGA study and our study in terms ofpatient characteristics, especially histologic type, the proportion ofpatients with HER2 IHC 3 þ tumours, and exclusion of patientswith performance status X2, trastuzumab may be a good addition
to a S-1-based regimen. Experimental studies have reported thattrastuzumab induces downregulation of thymidylate synthase
expression. This mechanism has been implicated in the synergistic
antitumour effect of S-1 plus trastuzumab against gastric cancer
cell lines that overexpress HER2 (Tanizaki et al, 2010). Capecitabine and S-1 are both 5-FU derivatives, but were developed
based on different concepts. Further studies of biomarkers andother predictors of outcomes are necessary to optimise the use of
these drugs.
During the planning phase of this trial, a 5-week cycle of SP
therapy was the mainstay of chemotherapy for AGC in Japan,
based on the results of the SPIRITS study (Koizumi et al, 2008).
As a molecular-targeted agent was combined with SP, thedevelopment of a 3-week cycle was planned. Results of phase II
studies of a 3-week regimen of SP have been reported in gastricwww.bjcancer.com | DOI:10.1038/bjc.2014.18

Trastuzumab/S-1/CDDP in gastric cancer

BRITISH JOURNAL OF CANCER

Table 3. Adverse events (n ¼ 53)

Grade
3

4

Any
(%)

18

3

1

74

8

5

14

5

60

36

0

0

1

1

4

4

5

22

6

2

66

15

Event

1

2

Leukopaenia

17

Neutropaenia

8

Febrile neutropaenia
AnaemiaGrade
3–4 (%)

Thrombocytopaenia

20

6

0

0

49

0

Anorexia

15

15

12

0

79

23

Fatigue

18

14

2

0

64

4

Nausea

20

12

1

0

62

2

Hypoalbuminaemia

14

6

5

0

47

9

Hypertension

9

12

1

0

42

2

Creatinine increased

21

0

3

0

45

6

Diarrhoea

10

7

4

0

40

8

Oral mucositis

10

6

1

0

32

2

Skin rash

12

1

0

0

25

0

Vomiting

7

3

3

0

25

6

ALT increased

11

2

0

0

25

0

Constipation

7

4

0

0

21

0

Dysgeusia

7

3

0

0

19

0

AST increased

9

0

0

0

17

0

Blood bilirubin increased

6

2

0

0

15

0

Edema

6

2

0

0

15

0

Peripheral sensory
neuropathy

1

5

0

0

11

0

Epistaxis

3

1

0

0

8

Hiccups

4

0

0

0

8

0

Fever

2

2

0

0

8

0

Infusion-related reaction

0

3

0

0

6

0

Alopecia

2

1

0

0

6

0

Abdominal pain

1

2

0

0

6

0

Skin hyperpigmentation

2

1

0

0

6

0

0

Abbreviations: ALT ¼ alanine aminotransferase; AST ¼ aspartate aminotransferase.

cancer and lung cancer (Lee et al, 2008; Choi et al, 2010; Kubota
et al, 2010). Recently, a phase III trial comparing the standard
5-week cycle of SP with a 3-week cycle of SP was conducted inpatients with AGC. This trial showed that the median PFSs in the
3-week and 5-week cycle groups were 5.5 and 4.9 months,
respectively, and it concluded that a 3-week cycle of SP wassuperior to a 5-week cycle of SP in terms of PFS (P ¼ 0.042) (Ryuet al, 2013). We therefore expected that a 3-week regimen of SP
plus trastuzumab would be more effective than a 5-week regimen
of SP plus trastuzumab. Although the dose intensity of cisplatin(20 mg m  2 per week) in a 3-week SP regimen was 25% lower thanthat (26.7 mg m  2 per week) in the ToGA study regimen, the RR(48%) of 3-week SP regimen was higher than that (35%) of the
ToGA regimen. Thus, we considered that the dose (60 mg m  2) ofcisplatin was adequate in this 3-week SP regimen.
In this study, we limited subjects to patients with measurable
lesions assessable according to RECIST guidelines (version 1.1).
In clinical practice, however, many patients with gastric cancer
have no measurable lesions, such as those with peritoneal
www.bjcancer.com | DOI:10.1038/bjc.2014.18

metastasis. We are therefore conducting another phase II study
in patients who have HER2-positive AGC without measurable
lesions (HERBIS-1B; UMIN000007941) to confirm the usefulnessof this regimen in this subgroup.
In conclusion, although this was not a randomised controlled
study, our results suggest that SP plus trastuzumab has a good
toxicity profile and promising efficacy, justifying the further studyof regimens that contain SP and trastuzumab.

ACKNOWLEDGEMENTS

This work was supported by Taiho Pharmaceutical. This study was
conducted as a collaborative effort of the Osaka Gastrointestinal
Cancer Chemotherapy Study Group (OGSG), Hokkaido Gastrointestinal Cancer Study Group (HGCSG), and Tohoku ClinicalOncology Research and Education Society (T-CORE). We areindebted to the last Professor Hiroya Takiuchi, who played apivotal role in this study. We thank Y Sato and H Hagimoto who
provided editorial support on behalf of Taiho Pharmaceutical.

CONFLICT OF INTERESTY Kurokawa, H Imamura, Y Komatsu, Y Doki, and T Tsujinaka
received speaker honoraria from Taiho Pharmaceutical.
Y Komatsu and Y Doki received unrestricted research grant from
Taiho Pharmaceutical. The remaining authors declare no conflictof interest.

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www.bjcancer.com | DOI:10.1038/bjc.2014.18