Evaluation of lung adverse events with trastuzumab using the Japanese pharmacovigilance database

The present study aimed to determine the risk of trastuzumab-induced lung toxicity, time to onset, and post hoc outcomes using the Japanese Adverse Drug Event Report database. We analyzed data for the period between April 2004 and March 2021. Data on lung toxicities were extracted, and relative risk of adverse events (AEs) was estimated using the reporting odds ratio. We analyzed 1,772,494 reports and identified 4362 reports of AEs caused by trastuzumab. Of these, 693 lung toxicities were reportedly associated with trastuzumab. Signals were detected for seven lung toxicities: interstitial lung disease, pulmonary edema, pleural effusion, lung disorder, acute pulmonary edema, pulmonary fibrosis, and radiation pneumonitis. Among these, interstitial lung disease was the most frequently reported (61.8%). A histogram of times to onset showed occurrence from 1 to 105 days, but some cases of interstitial lung disease occurred even more than one year after the start of administration. The AEs showing the highest fatality rates were interstitial lung disease, pulmonary fibrosis, and radiation pneumonitis. This study focused on lung toxicities caused by trastuzumab as post-marketing AEs. Some cases could potentially involve serious outcomes; therefore, patients should be monitored for signs of the onset of these AEs not only at the start of administration, but also over an extended period, especially for interstitial lung disease.


Introduction
Trastuzumab is a monoclonal antibody against human epidermal growth factor receptor 2 (HER2) [also known as ERBB2 (receptor tyrosine-protein kinase erB-2)] [1]. Combination chemotherapy with trastuzumab improves the survival of patients with several metastatic carcinomas [1][2][3][4][5][6]. In Japan, trastuzumab has been approved for the treatment of advanced solid tumors, including breast cancer, gastric cancer, colorectal cancer, and salivary gland cancer. Trastuzumab has been used in combination with chemotherapy and has been reported to prolong both overall and progressionfree survival in clinical trials [1][2][3][4][5][6]. However, trastuzumab can cause a variety of adverse events (AEs). Among these, cardiac disorder is the most common serious AE, and others include infusion reaction and interstitial pneumonia/pulmonary disorder [7][8][9][10]. Cardiac impairment has been reported in previous studies as a mostly reversible AE [11,12]. In contrast, lung-specific AEs attributable to trastuzumab have received little attention in clinical trials, despite their potentially life-threatening potential. Furthermore, even though trastuzumab has been widely used in patients since its launch, detailed information on lung-specific AEs from post-marketing monitoring has not been reported. Inadequate management of AEs may force discontinuation of trastuzumab treatment until the events can be controlled, which may in turn incur disadvantages to the patient, such as decreased efficacy. We therefore conducted this study to examine time to onset, incidence rates, and outcomes of 1 3 219 Page 2 of 9 trastuzumab-induced AEs associated with lung toxicity in patients with cancer, based on information obtained from the spontaneous reporting system in the Japanese Adverse Drug Event Report (JADER) database of the Pharmaceuticals and Medical Devices Agency (PMDA).

Data source
Healthcare professionals and pharmaceutical companies send AE reports to the PMDA. Information was obtained from the JADER database [13][14][15][16] on the PMDA website (https:// www. pmda. go. jp/ engli sh/ index. html, https:// www. info. pmda. go. jp/ fukus ayoudb/ CsvDo wnload. jsp), which includes AE cases. All data from the JADER database were fully anonymized by the regulatory authority before we accessed them. All methods were thus performed in accordance with the relevant guidelines and regulations. We analyzed AE reports recorded between April 2004 and March 2021. The data structure of the JADER consists of four datasets: patient demographic information (DEMO); drug information (DRUG); AEs (REAC); and medical history (HIST). AEs in the JADER database are coded according to the preferred terminology of the Medical Dictionary for Regulatory Activities/Japanese, version 24.1 (www. pmrj. jp/ jmo/ php/ indexj. php).
We first removed duplicate cases from the DRUG and REAC tables using the methods described by Hirooka and Yamada [16]. We then used the identification number of each AE case to merge corresponding case data from the DRUG, REAC, and DEMO tables. The contributions of medications to AEs were classified as "suspected medicine," "concomitant medicine," and "interaction." Only those cases classified as "suspected medicine" were extracted.
To investigate the associations between trastuzumab and lung AEs, we analyzed the JADER database, which contains spontaneous AE reports submitted to the PMDA.

Statistical analyses
Data on lung AEs with more than five reported cases were extracted, and the relative risk of AEs was estimated using the reporting odds ratio (ROR). ROR is frequently used in the spontaneous reporting database as an indicator of the relative risk of AEs. We used the analysis data table and constructed 2 × 2 tables based on two classifications: presence or absence of "lung AEs"; and presence or absence of suspected trastuzumab use. The ROR was calculated by dividing the reported rate of AEs attributable to trastuzumab by the reported rate of the same AEs attributable to all other drugs in the database. The signal of AEs was considered positive if the lower limit of the 95% confidence interval (95%CI) of the ROR was > 1 [17]. The data on lung AEs related to trastuzumab were further divided into two groups according to with or without of concomitant medication, and the ROR was calculated and compared for each group. P-values were calculated using Fisher's exact test.
The time to onset of AEs was calculated and the number of cases was counted for reports in which the date of onset of AEs, the date of start of administration, and the date of end of administration were described as year/month/ day or year/month [5]. The onset time was calculated as "(onset date of AE)-(administration start date) + 0.5" in principle [18]. If there was a period of non-administration for more than one year, the date of first administration of the most recent continuous administration period was used. The time to onset of AEs for analysis was limited to 2 years (730 days). The Weibull distribution is represented by scale parameter α and shape parameter β. The scale parameter α represents the scale of the distribution function, as the quantile in which 63.2% of AEs occur [19]. A large value for this parameter indicates a wide distribution, while a small value indicates a narrow distribution. The shape parameter β represents the change in hazard over time in the absence of a reference population. Depending on the value of shape parameter β, an upper limit of the 95%CI for β < 1 indicates that the hazard increases initially and then decreases (early failure type). Conversely, a β value containing 1 or almost 1 and a 95%CI including 1 indicates that the hazard remains constant throughout the exposure period (random failure type) and a lower limit of the 95%CI for β > 1 indicates that the hazard increases over time (wear-out failure type). All statistical analyses were performed using JMP Pro® version 16.1 (SAS Institute, Cary, NC, USA).

Incidence of lung AEs with trastuzumab
We joined the three tables of DRUG (3,875,874 reports), REAC (1,096,193 reports), and DEMO (693,295 patients) by ID number. We removed duplicate data from the DRUG and REAC tables [20]. The causes of ADRs fall into three categories: "suspected drug," "concomitant drug," and "interaction." Of these, all data included in the category of "suspected drug" were extracted and used as the "data table" (1,772,494 reports).
We analyzed this data table and obtained 4362 reports of AEs attributed to trastuzumab. Of these, 693 lung AEs were reportedly associated with trastuzumab (Fig. 1). The patient characteristics are shown in Table 1. Approximately 84.7% of patients were female. According to the age distribution of the study population, pulmonary toxicity occurred frequently among individuals in their 60 s (38.4%).

Time to onset of lung AEs with trastuzumab
Histograms of the times to onset of the seven detected lung AE signals showed that AEs occurred from 1 to 105 days after trastuzumab administration (Fig. 2). Median time to onset was 75 days [interquartile range (IQR) 43-112 days] for interstitial lung disease, 56 days (IQR 55-92 days) for pulmonary edema, 18 days (IQR 8-85 days) for pleural effusion, 105 days (IQR 92-190 days) for lung disorder, 1 day (IQR 1-31 days) for acute pulmonary edema, 87 days (IQR 45-129 days) for pulmonary fibrosis, and 85 days (IQR 85-85 days) for radiation pneumonitis caused by trastuzumab. The Weibull distribution of histograms of time to onset showed that the range of 95%CIs for shape parameter β of interstitial lung disease, pleural effusion, and acute  pulmonary edema were β < 1, while other AEs were β > 1 ( Table 4).

Outcomes after occurrence of AEs
The percentages of outcomes (recovery, remission, not recovered, with sequelae, death, unclear) after the onset of seven AEs are shown in Fig. 3. Fatal outcomes were observed for interstitial lung disease, pleural effusion, pulmonary edema, pulmonary fibrosis, and radiation pneumonitis.

Discussion
This study focused on lung toxicities caused by trastuzumab and those AEs for which signals were detected were interstitial lung disease, pulmonary edema, pleural effusion, lung disorder, acute pulmonary edema, pulmonary fibrosis, and radiation pneumonitis. Among these, interstitial lung disease was the most frequently reported (61.8%, 428/693) and fatal cases were also reported. The Weibull distribution showed that the incidence of interstitial lung disease developed early after trastuzumab administration. Interstitial lung disease caused by trastuzumab has been reported in clinical trials [21][22][23] and the results of the present study are consistent with the clinical findings. In previous studies, interstitial lung disease has shown a high mortality rate if untreated, and early diagnosis and treatment are known to significantly reduce mortality [24]. In this study, although the incidence of interstitial lung disease did not increase in a dose-dependent manner, continuous monitoring is recommended throughout the entire treatment period, as some cases were observed during longterm treatment. On the other hand, the risk of developing interstitial lung disease is less than that of Fam-trastuzumab deruxtecan, a novel antibody-drug conjugate that combines trastuzumab with a topoisomerase I inhibitor [25,26]. However, since the interstitial lung disease caused by trastuzumab is often associated with fatal outcomes, clinicians should pay close attention to its development.
Of the seven AEs for which signals were detected, fatal outcomes were observed in five. Of these, fatal cases of pleural effusion, pulmonary edema, pulmonary fibrosis, and radiation pneumonitis were observed for interstitial lung disease. Both pleural effusion and interstitial lung disease occur early after trastuzumab administration. Among the reported cases, median time to the onset of pleural effusion was 18 days. Clinicians should be alert to the development of pleural effusion, particularly in the initial stages of trastuzumab administration. The incidences of pulmonary edema and pulmonary fibrosis developed Table 2 Numbers of reports and RORs of lung adverse events related to trastuzumab "Cases" indicate the number of reported cases of pulmonary toxicity. ROR, reporting odds ratio; 95% CI, 95% confidence interval. Italicized p-values represent statistically significant results. We used more than five reports for each type of pulmonary toxicity. All analyzed data were obtained from the Japanese Adverse Drug Event Report database. The hypothesis tests were two-sided and statistical significance was set at the level of p < 0.05. P-values were calculated using Fisher's exact test  The results of the present study must be considered in light of some limitations. First, the JADER database is based on self-reported data, which may contribute reporting biases, such as over-and underreporting. Second, the lack of comprehensive medical records and medication histories limits the scope of the analysis, as details of the trastuzumab dosage and duration of use remain unknown. Third, we could not rule out the possibility that AEs may have been caused by concomitant medications, not only chemotherapeutic agents as well as supportive care medications such as antiemetics (aprepitant, granisetron), analgesics, antihistamines, or medications prescribed for comorbidities, such as diabetes and hypertension. Nevertheless, in most of the RORs, including the ROR for interstitial lung disease, there was not any difference between with and without concomitant medications, suggesting that there was little effect of concomitant medications. Fourth, potential con founding, selection, and information biases cannot be fully excluded from this study. However, the results of this study were based on extracted data in which trastuzumab was judged to be the suspect drug by the reporter (physician or pharmacist) who knew the details of the clinical course. Thus, our report provides useful information for monitoring AEs of lung toxicity caused by trastuzumab.
In conclusion, we focused on lung toxicities caused by trastuzumab as post-marketing AEs. Interstitial lung disease, pleural effusion, pulmonary edema, pulmonary fibrosis, and radiation pneumonitis could potentially result in serious outcomes after administration of trastuzumab, and interstitial lung disease in particular still occurred even more than one year after administration. Patients should be monitored for signs of the onset of these AEs not only at the start of administration, but also over an extended period, especially for interstitial lung disease. Clinicians need to be aware of the potential for the development of these AEs for a long period after trastuzumab administration. Cases" indicate the number of reported cases of adverse events associated with trastuzumab. ROR: reporting odds ratio. ROR set to 1 for without co-medication. 95% CI: 95% confidence interval. Co-medication: concomitant medication. Italicized p-values represent statistically significant results. The hypothesis tests were 2-sided, and statistical significance was set at p < 0.05. P-values were calculated using Fisher's exact test