Analysis of Adverse Events Associated with Trastuzumab Deruxtecan in Patients with Gastric and Breast Cancer: A Retrospective Study

Abstract

Trastuzumab deruxtecan (T-DXd) has displayed demonstrable efficacy and manageable toxicity in previously treated patients with advanced gastric and breast cancer, and it has been approved in Japan. However, there is a lack of data on the optimal management in clinical practice. Therefore, we assessed the adverse event (AE) profiles of T-DXd in patients with advanced gastric or breast cancer to provide guidance for appropriate management. This retrospective study was conducted at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. We reviewed the medical records of patients with advanced gastric or breast cancer who received T-DXd between May 2020 and December 2021. AEs occurring within the first three cycles of T-DXd were evaluated according to Common Terminology Criteria for Adverse Events version 5.0. Thirty-six patients were enrolled (gastric: n = 19, breast: n = 17). All 15 males had gastric cancer, whereas 4 and 17 females had gastric and breast cancer, respectively. Interstitial lung disease (ILD) occurred in five patients (14%), but no patients had severe ILD. Gastrointestinal (GI) toxicities, including nausea (61%), vomiting (22%), decreased appetite (33%), and diarrhea (39%), were the most common AEs. The incidence of GI toxicities did not differ by cancer type; however, nausea was significantly more common in females (81 vs. 33%; p < 0.01). T-DXd was safely administered in clinical practice in patients with previously treated advanced gastric or breast cancer. The management of GI toxicities is important in the clinical implementation of T-DXd.

INTRODUCTION

Trastuzumab deruxtecan (T-DXd) is an antibody–drug conjugate that combines an antibody targeting human epidermal growth factor type 2 (HER2) with a topoisomerase I inhibitor. After specific binding and intracellular uptake by HER2-expressing tumor cells, the drug is released, and it exerts its antitumor effect through the inhibition of topoisomerase I.^1–3) Based on the results of clinical trials in breast cancer (BC; DESTINY-Breast 01, DESTINY-Breast 02, DESTINY-Breast 03, DESTINY-Breast 04^4–7)) and gastric cancer (GC; DESTINY-Gastric 01⁸⁾), T-DXd was approved for the treatment of HER2-positive or HER2-low inoperable or recurrent BC and HER2-positive inoperable advanced or recurrent GC in several countries including Japan. According to clinical trials on T-DXd-related adverse events (AEs), the most critical AE was interstitial lung disease (ILD), and some treatment-related deaths were reported. Importantly, Japanese patients had a higher incidence of ILD than non-Japanese patients.^4–8) Nausea and vomiting were the most frequently observed AEs in clinical trials.^4–8) Thus, understanding the incidence of ILD and managing gastrointestinal (GI) toxicities are crucial for the effective utilization of T-DXd in clinical practice.

The emetic risk for T-DXd differs between Japan and other countries, with the National Comprehensive Cancer Network (NCCN) guidelines classifying it as highly emetogenic and the Japanese guidelines classifying it as moderately emetogenic.^9,10) This difference is a point of concern in clinical practice. The Japanese antiemetic guidelines state that it is important to accumulate clinical data. In recent years, pharmacists have been strongly urged to be actively involved in cancer chemotherapy with the introduction of pharmacist outpatient clinics. The important roles of pharmacists include providing patients with information on side effects and suggesting drugs to alleviate such AEs.^11,12) However, the most appropriate antiemetic for T-DXd is unknown, and pharmacists’ suggestions for supportive care can vary. Additionally, although clinical trials have reported a higher incidence of ILD in Japanese patients, it is unclear whether ILD is an equally important adverse event in actual clinical practice.

In this study, we retrospectively investigated T-DXd-associated AEs with a special focus on ILD and GI toxicities in patients with BC and GC. Furthermore, we attempted to identify appropriate antiemetic suggestions for GI toxicity attributable to T-DXd in the pharmacist outpatient setting.

MATERIALS AND METHODS

Study Design and Treatment

This retrospective, observational study was conducted at a Japanese institute between May 2020 and December 2021. Patients meeting the following eligible criteria were enrolled: 1) histologically proven HER2-positive gastric adenocarcinoma or HER2-positive or HER2-low breast adenocarcinoma, 2) inoperable advanced or recurrent stage tumors, 3) receipt of T-DXd monotherapy in clinical practice, 4) prior receipt of at least two chemotherapy regimens, 5) adequate main organ function, and 6) provision of informed consent for treatment. The treatment schedules and dosages of T-DXd were as described in pivotal clinical trials (6.4 mg/kg in GC and 5.4 mg/kg in BC).

Data Collection

We reviewed the electronic medical record (EMR) and collected baseline patient characteristics and the incidence of hematological (leukopenia, neutropenia, lymphopenia, and thrombocytopenia) and GI toxicities (nausea, vomiting, anorexia, and diarrhea) and ILD during the first three cycles. The starting dose and dose reduction were investigated in each course of treatment. The use of antiemetic agents was investigated in each treatment cycle. The AE grade was evaluated following the Common Terminology Criteria for Adverse Events version 5.0.

Statistical Analysis

Differences in the incidence of GI and hematological toxicities by cancer type were examined using Student’s t-test, as were sex differences between males and females.

The incidence rates of hematologic toxicities, GI toxicities, and ILD were compared between cancer types (GC vs. BC) and sexes (female vs. male) using Fisher’s exact test. The level of statistical significance was set at p < 0.05. Statistical analyses were performed using SPSS version 24 (IBM Corp., Armonk, NY, U.S.A.).

Ethical Considerations

This study was approved by the Clinical Research Ethics Review Committee of the Cancer Institute Hospital, Japanese Foundation for Cancer Research (Approval Number: 2021-GB-096).

RESULTS

Patient Characteristics

Between May 2020 and December 2021, 36 consecutive patients (GC: n = 19, BC: n = 17) were enrolled in this study. The patient characteristics are presented in Table 1. All 15 males had GC, whereas 4 and 17 females had GC and BC, respectively. The median age of all patients was 65 years, including median ages of 68 years (range: 40–79) for patients with GC and 59 years (range: 49–79) for patients with BC. All patients in this study had a HER2 IHC score of 2+ or 3+. Eight patients (42.1%) with GC previously underwent gastrectomy. The median number of treatment cycles for all patients was six (range: 1–18), and the median numbers of cycles were five (range: 1–19) for patients with GC and nine (range: 1–10) for patients with BC.

Table 1. Clinical Characteristics of Patients at Baseline

	All (n = 36)	Gastric (n = 19)	Breast (n = 17)
Median age (range)	65 (40–79)	68 (40–79)	59 (49–79)
Sex—No. (%)	65	68	59
Male	15 (42)	15 (79)	0 (0)
Female	21 (58)	4 (21)	17 (100)
ECOG performance status—No. (%)
0	13 (36)	7 (37)	6 (35)
>=1	23 (64)	12 (63)	11 (65)
HER2 expression—No. (%)
IHC3+	28 (78)	13 (68)	15 (88)
IHC2+ or ISH-positive	8 (22)	6 (32)	2 (12)
Disease status—No. (%)
IV	14 (39)	12 (63)	2 (12)
Recurrence	22 (61)	7 (37)	15 (86)
Gastrectomy—No. (%)
Yes		8 (42)
No		11 (58)
Number of previous treatments—No. (%)
2	14 (39)	11 (58)	3 (18)
>=3	22 (61)	8 (42)	14 (82)
Metastatic site—No. (%)
Lymph node	12 (33)	7 (37)	5 (29)
Peritoneum	13 (36)	11 (58)	2 (19)
Liver	14 (39)	9 (47)	5 (29)
Lung	13 (36)	5 (26)	8 (47)
Bone	8 (22)	3 (16)	5 (29)

ECOG, Eastern Cooperative Oncology Group.

Incidence of AEs

The incidence of AEs for all patients, as well as patients with GC and BC, is summarized in Table 2. ILD was reported in five patients (14%), and all cases were graded as mild-to-moderate. The incidence of GI and hematological toxicities did not differ between the BC and GC groups (Figs. 1a, b). Furthermore, GI and hematologic toxicity did not differ between males and females with GC (Figs. 1c, d). A detailed analysis of nausea revealed that the incidence of nausea was grade 2 or higher in females but grade 2 or lower in males (Fig. 1f). The incidence of hematological toxicity was similar between males and females, whereas GI toxicity was significantly more common in females than in males (p = 0.03, Figs. 2a, b). Among GI toxicities, a sex difference was found for nausea and vomiting (p < 0.01). No significant difference was observed in the rates of decreased appetite and diarrhea between males and females (Fig. 2c).

Table 2. Incidence of Side Effects in all Patients

No. (%)	All (n = 36)		Gastric (n = 19)		Breast (n = 17)
	Any grade	Grade 3	Any grade	Grade 3	Any grade	Grade 3
Nausea	22 (61)	3 (8)	8 (42)	1 (5)	14 (82)	2 (12)
Vomiting	8 (22)	0 (0)	3 (16)	0 (0)	5 (29)	0 (0)
Decreased appetite	12 (33)	1 (3)	7 (37)	0 (0)	5 (29)	1 (6)
Diarrhea	14 (39)	0 (0)	7 (37)	0 (0)	7 (41)	0 (0)
Interstitial lung disease	5 (14)	0 (0)	3 (16)	0 (0)	2 (12)	0 (0)
White cell count decreased	17 (47)	0 (0)	8 (42)	0 (0)	9 (53)	0 (0)
Neutrophil count decreased	21 (58)	1 (3)	9 (47)	0 (0)	12 (71)	1 (6)
Lymphocyte count decreased	20 (56)	4 (11)	8 (42)	4 (21)	12 (71)	0 (0)
Platelet count decreased	14 (39)	0 (0)	5 (26)	0 (0)	9 (53)	0 (0)
Anemia	31 (86)	2 (6)	16 (84)	2 (11)	15 (88)	0 (0)
AST elevated	4 (11)	0 (0)	2 (11)	0 (0)	2 (12)	0 (0)
ALT elevated	4 (11)	0 (0)	3 (16)	0 (0)	1 (6)	0 (0)
T-Bill elevated	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)	0 (0)

AST, aspartate aminotransferase; ALT, alanine aminotransferase; T-bil, total bilirubin.

Fig. 1. Incidence of GI Toxicity and Hematological Toxicity in the First Three Cycles

(a, b) Each side effect shown by cancer type. (c, d) Each side effect in patients with gastric cancer by sex. (f) Incidence of nausea by grade in patients with gastric cancer stratified by sex. Statistical analysis was performed using Fisher’s exact test (* p < 0.05).

Fig. 2. Sex Differences in the Incidence of GI Toxicity in the First Three Cycles

(a, b) Each side effect shown by sex. (c) The incidence of nausea, vomiting, decreased appetite, and diarrhea is presented by sex. Statistical analysis was performed using Fisher’s exact test (* p < 0.05).

Treatment Details

Patients who were able to complete the first three cycles with grade 0 or grade 1 nausea were analyzed (Fig. 3a). Of the six patients who completed the study with grade 0 nausea, 67% required dose reduction of T-DXd (Fig. 3a, left panel). Meanwhile, eight of nine patients who completed the procedure with grade 1 or lower nausea did not require dose reduction, but they completed treatment with the addition of antiemetic drugs or a change of the type of antiemetic drugs (Fig. 3a, right panel). Among the 28 patients who completed three cycles of T-DXd, 22 and 7% of patients required dose reduction in the second and third cycles, respectively (Fig. 3b). In the second cycle, 60% of the patients received a reduced dose of T-DXd because of GI toxicities (Fig. 3b, left panel), whereas GI toxicity was the reason for dose reduction in all patients in the third cycle (Fig. 3b, right panel).

Fig. 3. Reasons for T-DXd Dose Reduction

(a) The percentage of patients requiring T-DXd dose reduction among those who completed the first three cycles with grade 1 or lower nausea. (c) The pie chart presents the percentage of patients who required dose reduction during T-DXd treatment and the reasons for dose reduction. The left and right panels present the start of the second and third cycles, respectively. Each pie chart presents the percentage of patients requiring dose reduction on the left and the breakdown of reasons on the right.

Use of Antiemetic Drugs

Palonosetron (0.75 mg) and dexamethasone (6.6 mg) were intravenously administered as the standard premedication for all patients before T-DXd administration. The use of aprepitant, olanzapine, and additional oral dexamethasone was based on the attending physician’s discretion. The number of antiemetic drugs added to the standard premedication was verified for each cycle, as presented in Fig. 4. The number of antiemetic drugs used was higher for males than for females starting early in treatment (Fig. 4). Conversely, females tended to be treated with standard antiemetics in the first cycle, and the number of antiemetics used increased with each treatment cycle. Details of the antiemetic drugs that were added are presented in Table 3.

Fig. 4. Antiemetic Usage in the First Three Cycles

The use of antiemetic drugs during the first three cycles of T-DXd treatment is presented.

Table 3. Details of Antiemetic Drug Use

		1 cycle (No. (%))		2 cycle (No. (%))		3 cycle (No. (%))
		Female	Male	Female	Male	Female	Male
No additions		11 (61)	1 (10)	7 (39)	1 (10)	9 (50)	2 (20)
Add 1 drug	Apr	2 (11)	1 (10)	—	1 (10)	—	1 (10)
	Ola	4 (22)	—	5 (28)	—	2 (11)	—
	Dex	—	4 (40)	—	4 (40)	—	3 (30)
Add 2 drugs	Apr + Ola	—	—	3 (17)	—	1 (6)	—
	Apr + Dex	—	2 (20)	2 (11)	2 (20)	3 (17)	2 (20)
	Ola + Dex	1 (6)	2 (20)	1 (6)	2 (20)	2 (11)	2 (20)

Apr, aprepitant; Ola, olanzapine; Dex, dexamethasone.

DISCUSSION

The present study illustrated that patients with advanced GC and BC can be safely treated with T-DXd in clinical practice.^4–8) Importantly, no cases of serious ILD occurred in the first three cycles. The incidence of GI toxicities varied between males and females but not between GC and BC. The small number of females in the analysis of patients with GC should be considered a limitation of the study. However, more severe nausea appeared in females than in males. This suggests the existence of sex differences in the appearance of nausea. In addition, GI toxicities represented a main cause of T-DXd dose reduction, suggesting that appropriate management for GI toxicities is crucial for utilizing T-DXd in daily practice. Although not directly comparable, in patients with BC, the incidence of hematologic toxicity (92%) was higher in this study than in clinical trials (48%).⁴⁾ This can be explained that the fact that more patients treated in later lines of therapy were included in this study. The median number of prior treatments was six cycles (range: 2–27) in the clinical trial, versus nine cycles (range: 1–10) in this study.⁴⁾ In addition, the median age in the clinical trial was 55 years (range: 28–96), compared with 59 years (range: 49–79) in the present study.⁴⁾ Factors related to bone marrow exhaustion might explain the higher incidence of hematological adverse events in the present study than in clinical research.

The incidence of GI toxicities in this study was comparable to that in clinical trials.^4,8) Notably, a sex difference in the incidence of GI toxicities was clearly observed in this study. Importantly, GI toxicities represented the main reason for T-DXd dose reduction. Thus, appropriate management of GI toxicities might contribute to maintaining the dose intensity of T-DXd. Various factors such as female sex, young age, and no history of alcohol consumption were previously reported to be associated with a higher emetic risk in investigations of other anticancer drugs.^13–17) Sex hormones regulate the ABC transporters, and they might affect the absorption, distribution, and excretion of drugs.^18–22) However, a sex difference in the incidence of GI toxicities was not previously reported. Furthermore, there were several disparities related to the risk of GI toxicities between males and females in this study. More male patients received additional antiemetic agents on top of the standard antiemetic agents of palonosetron (0.75 mg) and dexamethasone (6.6 mg). According to NCCN guidelines,⁹⁾ the combination of four antiemetic agents (namely a 5-HT3 receptor antagonist, an NK1 receptor antagonist, dexamethasone, and olanzapine) is recommended during using T-DXd. In this study, an NK1 receptor antagonist was added for four patients who developed grade 2 or higher severe nausea in the first cycle. In two of these patients, nausea improved to grade 1 or lower in the second cycle (data not shown). Considering these facts, we believe it is reasonable to aggressively prescribe NK1 receptor antagonists or olanzapine to female patients at high risk of emesis in an outpatient setting from the start of T-DXd.

Because some patients died of ILD in clinical trials, ILD is a crucial concern in the implementation of T-DXd in clinical practice.²³⁾ The incidence of ILD in Japanese patients was reported to be 33.3% in the DESTINY-Breast 01 trial, 22.1% in the DESTINY-Breast 03 trial, 26.8% in the DESTINY-Breast 04 trial, and 11.1% in the DESTINY-Gastric 01 trial, indicating a high incidence.^4,6–8) Therefore, learning from treatment-related deaths in clinical trial, the emergence of ILD was observed with caution after approval in clinical practice. T-DXd discontinuation was highly recommended in patients with grade ≥1 ILD.²⁴⁾ In actual clinical practice, we must discontinue T-DXd in patients with ILD despite its demonstrated efficacy. After disease progression, it was recommended to consider switching to a different anticancer agent rather than resuming T-DXd. Further research is warranted to investigate the specific findings on CT that are associated with the development of critical ILD.

Finally, one limitation of this study was its small, retrospective, single-institute nature. Consequently, two biases are acknowledged. First, the information was collected from the EMR, and thus, the frequency of non-hematological toxicities was not accurately recorded. Second, it was not possible to identify independent risk factors for nausea and vomiting.

In conclusion, the results of our study were comparable to those of clinical trials. In clinical practice, T-DXd could be administered without serious ILD. Among the side effects, GI toxicity, as with other anticancer agents, was suggested to exhibit sex differences in its occurrence. It was also indicated that the onset of GI toxicity associated with T-DXd is a factor leading to reduced treatment intensity. Therefore, the addition of an antiemetic agent from the first dose might allow patients to continue treatment without decreasing the dose. From the pharmacist’s viewpoint, suggesting appropriate antiemetic drugs to the physician in light of the characteristics of the patient receiving T-DXd will be key to the continuation of treatment.

Conflict of Interest

The authors declare no conflict of interest.

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