Infusion Reactions in HER2-Positive Gastric Cancer: Switching from Trastuzumab to Its Biosimilar

Abstract

This study presents a safety analysis of infusion reactions (IRs) in gastric cancer patients who switched from reference trastuzumab to its biosimilar, trastuzumab-NK, at the Saitama Cancer Center in Japan from April 2018 to March 2022. IRs were identified if patients developed symptoms such as fever, chills, infusion-related reactions, hypersensitivity, rash, pruritus, urticaria, systemic disorders, or immune system disorders on the day of administration or the following day. The incidence of IRs was 14% in the reference trastuzumab group, 33% in the trastuzumab-NK group, and 33% in the switching group. There was no significant difference in IR incidence between the reference trastuzumab and trastuzumab-NK groups (p = 0.235). Among the switching group, only one of the three patients who experienced an IR had a reaction associated with the switch. These findings suggest that the frequency of IRs in the switching group gastric cancer is comparable to the other groups, indicating that switching is a viable treatment option with appropriate management. Additionally, 37 of the 45 patients in the study were male, provides new safety information on switching in gastric cancer for male patients that has not been previously reported.

INTRODUCTION

Trastuzumab, a biopharmaceutical, is used for treating human epidermal growth factor receptor type 2 (HER2)-positive breast and gastric cancers.^1,2) In Japan, HERCEPTIN^® (reference trastuzumab) was first approved for HER2-positive breast cancer in 2001 and for HER2-positive gastric cancer in 2011. Since then, several trastuzumab biosimilars have been launched, and data on their use and side effects in both breast and gastric cancers have been accumulated.^3–5) However, there is limited information on the safety of switching from HERCEPTIN^® to the trastuzumab biosimilar, causing hesitation in making the switch. In breast cancer treatment, trastuzumab is often used with the anti-HER2 antibody drug pertuzumab, making it challenging to identify the drug responsible if an infusion reaction (IR) occurs. A 2023 report discussed switching breast cancer patients using trastuzumab without pertuzumab,⁶⁾ but the information is only for female patients, leaving a gap in safety information for male patients.

In contrast, trastuzumab in gastric cancer therapy is often used with cytotoxic agents like FOLFOX and CapeOX,⁷⁾ making IR easier to evaluate as the treatment does not include other antibody drugs. However, it is crucial to focus on symptoms when evaluating IR, as concomitant cytotoxic agents may cause side effects like nausea and vomiting. A 2021 report by Saito et al. discussed the safety of switching for breast and stomach cancers, but only 6 of the 140 patients had stomach cancer, indicating a need for more information on switching for stomach cancer.⁸⁾ The ToGA study reported that events occurring on the day of or the day after HERCEPTIN^® administration were mainly fever, along with chills, hypersensitivity, epiphora, pruritus, urticaria, and fever.⁹⁾ Since the events that showed differences between the cytotoxic agents group and the cytotoxic agents group were systemic disorder, immune system disorder, and skin and subcutaneous tissue disorder, we believe that excluding these symptoms from the evaluation can provide more accurate IR information.

Given these backgrounds, we evaluated the safety of trastuzumab switching to gather IR information on 1) switching for gastric cancer and 2) male patients, which have been relatively less reported so far.

PATIENTS AND METHODS

Patients and Study Design

We conducted a retrospective review of the medical records of gastric cancer patients who received any regimen that included trastuzumab at the Saitama Cancer Center (Saitama, Japan) from April 2018 to March 2022. This study was approved by the institutional review board of Saitama Cancer Center (Approval No. 1311; approved December 12, 2021). The reference trastuzumab used was HERCEPTIN^® (Chugai Pharmaceutical Co., Ltd., Tokyo, Japan), whereas the biosimilar trastuzumab was Trastuzumab BS for I.V. Infusion 60/150 mg “NK”: Trastuzumab-NK (Nippon Kayaku Co., Ltd., Tokyo, Japan). On August 19, 2020, we switched from reference trastuzumab to trastuzumab-NK. Patients were categorized into three groups: a reference trastuzumab-only group, a group that switched from reference trastuzumab to trastuzumab-NK and continued treatment (switching group), and a trastuzumab-NK-only group. Patients who had previously received any antibody drugs or were receiving antibody drugs other than trastuzumab were excluded from the study.

Treatment

Trastuzumab was administered at a dosage of 8 mg/kg over 90 min for the first dose, followed by 6 mg/kg over 30 min for the second and subsequent doses, on a triweekly basis. The combination regimens with trastuzumab included FOLFOX, SP, CapeOX, SOX, Irinotecan, and S-1.

Survey Items

We recorded baseline patient characteristics such as age, sex, weight, body mass index (BMI), HER2 score, combination regimen, stages, dosing time, and IR expression status. For IR, the presence of Grade 1 or higher was evaluated based on the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE ver. 5.0). IR was considered present if the patient developed fever, chills, an infusion-related reaction, hypersensitivity, rash, pruritus, urticaria, systemic disorder, or an immune system disorder on the day of administration or the day after administration. Of those with an IR entry in the doctor’s or nurse’s medical record, those with an IR of G1 or above by CTCAE ver. 5.0 criteria were considered to have an IR. Skin and subcutaneous tissue disorders were excluded from the evaluation, as these side effects are more likely to occur with S-1 and capecitabine.

Statistical Analysis

Statistical analysis was performed using JMP 14 (SAS Institute, Cary, NC, U.S.A.). Patient characteristics and the expression of IR in the reference trastuzumab group and the trastuzumab-NK group were compared using the Fisher’s exact test or the Kruskal–Wallis test. p < 0.05 was considered to indicate a statistically significant difference. In addition, no statistical sample size calculations were conducted. However, a sample size of Reference trastuzumab group and Switching group gave post hoc powers of 19% to detect differences in the ratio of IR expression.

RESULTS

Baseline Clinical Characteristics

The study included 45 patients, with 21 in the reference trastuzumab group, nine in the switching group, and 15 in the trastuzumab-NK group (Table 1). There were no differences in patient background between groups. The combination regimens involved FOLFOX in 4 patients, SP in 1, CapeOX in 13, SOX in 23, S-1 in 3, and Irinotecan in 1. Dexamethasone was used as premedication: 9.9 mg for FOLFOX and SP, 6.6 mg for CapeOX and SOX, and none when combined with S-1. There were no changes in the premedication regimen.

Table 1. Baseline Patient Characteristics

	Reference trastuzumab group (n = 21)	Switching group (n = 9)	Trastuzumab-NK group (n = 15)	p-Value
Sex
Male	18	7	12	0.7813
Female	3	2	3
Age, years
Mean (S.D.)	69.0 (8.00)	67.0 (9.06)	70.0 (11.2)	0.5125
Median (range)	70.0 (53–79)	67.0 (51–81)	75.0 (51–85)
Weight, kg
Mean (S.D.)	55.2 (7.67)	54.1 (7.61)	52.5 (12.4)	0.7484
Median (range)	56.0 (38.9–67.1)	51.8 (44.0–65.8)	52.5 (42.5–94.4)
BMI
Mean (S.D.)	20.7 (2.31)	20.2 (1.88)	21.1 (3.04)	0.7903
Median (range)	20.8 (17.4–24.3)	20.1 (17.3–22.3)	20.4 (16.3–29.9)
HER2 score
+2	8	6	4	0.2101
+3	13	3	11
Stage
IA	0	0	0
IB	0	0	1
IIA	0	0	0
IIB	0	1	1
IIIA	0	0	0
IIIB	0	0	1
IIIC	0	1	0
IV	21	7	12
Combination regimen
FOLFOX (Premed: dex 9.9 mg)	2	0	2
SP (Premed: dex 9.9 mg)	1	0	0
CapeOX (Premed: dex 6.6 mg)	3	4	6
SOX (Premed: dex 6.6 mg)	13	4	6
S-1	1	1	1
Irinotecan	1	0	0

S.D., standard deviation.

IR Expression

IR of Grade 1 or higher was observed in three patients (14%) in the reference trastuzumab group, three patients (33%) in the switching group, and five patients (33%) in the trastuzumab-NK group (Table 2). There was no significant difference in IR expression between the reference trastuzumab group and the trastuzumab-NK group (p = 0.235). IRs were characterized by symptoms such as fever, chills, sore throat, difficulty breathing, fatigue, and cold sweat, occurring on the day of or the day after the start of treatment in all patients. Among the three patients in the switch group who developed an IR, one was as a result of the switch (Table 3). Of the 11 patients in whom IR occurred, 10 were inpatient and one was administered as an outpatient.

Table 2. Incidence of Infusion Reactions

	Reference trastuzumab group (n = 21)	Switching group (n = 9)	Trastuzumab-NK group (n = 15)	p-Value
Infusion reaction
Yes	3 (14%)	3 (33%)	5 (33%)	0.3149
Sex
Male	2	2	3
Female	1	1	2
Grade
G1	3	3	5
G2 or higher	0	0	0
No	18 (86%)	6 (67%)	10 (67%)
Sex
Male	16	6	6
Female	2	0	0

Table 3. Details of Infusion Reaction

	No.	Sex	Age	HER2 score	Stage	Combination regimen	Drugs	Adverse events	Timing of IR	Inpatient/outpatient
Reference trastuzumab group	1	F	52	3 +	IV	FOLFOX	Reference trastuzumab	Chill	15 min after administration	Inpatient
	2	M	79	2 +	IV	SOX	Reference trastuzumab	Chill	Administering	Inpatient
	3	M	77	3 +	IV	S-1	Reference trastuzumab	Fever	Administering	Inpatient
Switching group	4	M	70	2 +	IV	SOX	Reference trastuzumab	Fever, chill	3 h after administration	Inpatient
	5	F	81	3 +	IV	CapeOX	Reference trastuzumab	Fever	6 h after administration	Inpatient
	6	F	67	3 +	IIB	CapeOX	Biosimilar	Fever, sore throat	Immediately after administration	Outpatient
Trastuzumab-NK group	7	F	57	3 +	IV	SOX	Biosimilar	Difficulty breathing, fatigue	Immediately after administration	Inpatient
	8	M	71	3 +	IV	FOLFOX	Biosimilar	Fever	Immediately after administration	Inpatient
	9	M	75	3 +	IIIB	CapeOX	Biosimilar	Chill	Administering	Inpatient
	10	F	81	3 +	IV	CapeOX	Biosimilar	Fever, cold sweat	4 h after administration	Inpatient
	11	M	85	2 +	IV	FOLFOX	Biosimilar	Fever, chill	Administering	Inpatient

DISCUSSION

Trastuzumab-based regimens are recommended for primary treatment in HER2-positive advanced or recurrent gastric cancer.⁷⁾ The frequency of IRs associated with trastuzumab has been reported to be about 30% in gastric cancer,²⁾ and the incidence was similar across all groups in this study. Although it has been reported that stage progression is related to the occurrence of IR,¹⁰⁾ it is challenging to evaluate the use of trastuzumab for relatively early-stage disease, unlike breast cancer, because the indication for trastuzumab in Japan is for advanced or recurrent disease.

Trastuzumab was approved in Japan for the treatment of gastric cancer about a decade after its approval for breast cancer. Consequently, the lack of safety information on the trastuzumab biosimilar may be one of the reasons for hesitation in switching to trastuzumab for gastric cancer. However, the results of this study showed that the frequency of IRs in the group that switched from reference trastuzumab to trastuzumab-NK was similar (Table 2) to that in the reference trastuzumab group and the trastuzumab-NK group (Table 3). In the switching group, two of the three patients had IRs during reference trastuzumab treatment and one during biosimilar treatment, suggesting that the frequency of IRs in the switching group is similar to the other two groups. Of the nine patients in the switching group, only one (11%) developed an IR with trastuzumab-NK, and that patient did not develop an IR when receiving reference trastuzumab. No patient in the switching group developed an IR with both reference trastuzumab and trastuzumab-NK. This suggests that an IR with reference to trastuzumab may not necessarily be caused by switching to the biosimilar. Furthermore, the 11% result is comparable to or lower than the previously reported IR expression frequency of reference trastuzumab and trastuzumab-NK,¹¹⁾ suggesting that switching may be a viable treatment option from a safety perspective.

A significant concern with switching is the decision-making process at each facility regarding the dosing time for switching, whether it should be 30 min as a maintenance dose or 90 min as an initial dose. Safety reports on 30-min dosing during switching have been documented,^6,8) and there are reports suggesting that the onset of IR is related to the dose per unit of time.¹⁰⁾ Therefore, careful consideration is recommended when setting the dosing time. Specifically, the dosage and administration of trastuzumab in gastric cancer are limited to 8 mg/kg for the first dose and 6 mg/kg for the second and subsequent doses on a triweekly basis. Unlike breast cancer, there is no weekly dosage regimen of 4 mg/kg for the first dose and 2 mg/kg for the second and subsequent doses. As a result, control of the dose per unit of time requires control by rate of administration rather than dose. Other factors that may influence IR development include the presence or absence of premedication and differences in its content. However, these effects are small because the effectiveness of antihistamines, corticosteroids, and other drugs aimed at avoiding IR development is not clear. Depending on the individual circumstances of each patient, such as age and the nature of the concomitant regimen, it is advisable to pay sufficient attention to safety by setting a longer dosing time at the time of the initial switch or considering the contents of the premedication. Switching may be considered if administered under appropriate supervision. In addition, while most of the previous reports on trastuzumab IR have been in female patients and breast cancer patients,^6,8,12) the results of this study suggest that the risk of IR in male patients and patients with gastric cancer may be similar to those previously reported.

This study has certain limitations, including its single-center retrospective design and a limited number of cases. It is also possible that some symptoms that were excluded, such as skin and subcutaneous tissue disorders, could have been caused by trastuzumab rather than cytotoxic agents. Therefore, careful observation and evaluation of side effects are crucial in clinical practice. In addition, although a power analysis was performed based on a limited sample size, it cannot be said that this sample size has sufficient power. However, in terms of a preliminary report, we believe that we have provided valuable safety data on the incidence of IR in gastric cancer patients. Despite these limitations, the study has notable strengths. It provides valuable safety data on the incidence of IRs in gastric cancer patients who switched treatments, an area that has not been widely reported. Additionally, the study includes a significant number of male patients (37 out of 45), adding to the body of knowledge in this area. In terms of preliminary results, we believe that we have provided valuable safety data on the incidence of IR in gastric cancer patients. The findings of this study have the potential to expand the range of formulation choices in clinical practice, significantly contributing to reducing the economic burden on patients and improving healthcare economics.

Author Contributions

Conceived the study: TA; Designed the experiments: TA, AS, and DO; Analyzed the data: TA, AS, DO, KM, TS, and TN; Wrote the paper: TA and AS. All authors confirmed the authenticity of all the raw data, and provided intellectual input, and are responsible for the contents of the paper, including the data, analysis, and interpretation.

Conflict of Interest

The authors declare no conflict of interest.

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