T-DXd is becoming more broadly used for HER2-expressing or mutant cancers worldwide. As more patients use T-DXd in the future, the management of potential ILD/pneumonitis in T-DXd-treated patients is of prime importance. During the post-marketing period between May 25, 2020 and February 24, 2022, approximately 3000 patients received T-DXd; 287 of these patients (breast cancer: n = 207, gastric cancer: n = 80) were reported by their physician as potential ILD/pneumonitis cases, and 130 cases were evaluated as T-DXd-related ILD/pneumonitis (breast cancer: n = 101, gastric cancer: n = 29). The majority of cases adjudicated as T-DXd-related ILD/pneumonitis were grade 1 or 2, and 23.1% of cases were grade 3 or higher. The clinical outcomes varied by imaging pattern, suggesting that cases with DAD patterns have a poor prognosis and those with OP and HP patterns have favorable outcomes [11]. In addition, most ILD/pneumonitis cases that were treated with corticosteroids were considered responsive to treatment.

Although the pooled analysis of nine clinical trials reported the frequency of T-DXd-related ILD/pneumonitis to be 15.4% in patients treated with T-DXd [10], the currently available surveillance data suggest that the overall incidence of adjudicated T-DXd-related ILD/pneumonitis may be lower than the incidence previously reported. However, many patients enrolled in this surveillance were still within the observation period, meaning that not all potential ILD/pneumonitis cases have yet been identified or adjudicated; moreover, the outcomes of some ILD/pneumonitis cases were still being followed up at the data cutoff (February 27, 2022). Further investigation is needed to evaluate the overall incidence of adjudicated T-DXd-related ILD/pneumonitis in the post-marketing setting. Moreover, the lower rates of ILD/pneumonitis in patients with gastric cancer may also reflect the 6-month gap between approval of T-DXd for breast cancer and for gastric cancer in Japan. Importantly, we observed no noticeable increase in the incidence of ILD/pneumonitis compared with the incidence reported by the previous pooled analysis [10].

Many of the patients with gastric cancer and T-DXd-related ILD/pneumonitis had received prior treatment with ICIs (18/29, 62.1%). These patients did not have an earlier onset of ILD/pneumonitis or worse outcomes compared with those who had not received ICIs. The previous pooled analysis found no connection between prior treatment with ICIs and the frequency of ILD/pneumonitis [10]. Furthermore, this report was not designed to evaluate risk factors for ILD/pneumonitis. Therefore, it is currently unknown what effect this factor may have on ILD/pneumonitis risk.

Among the 130 adjudicated T-DXd-related ILD/pneumonitis cases that were evaluated, most cases (76.9%) had a low severity grade (1 or 2), which is similar to the previous pooled analysis [10]. We observed a spectrum of patterns including OP, HP, and DAD patterns. A similarly wide range of patterns was reported in earlier clinical trials [13] and studies of other anti-cancer drugs [11, 14]. No imaging pattern specific to T-DXd-related ILD/pneumonitis was observed in this report. We observed that the majority (8/11, 72.7%) of fatal ILD/pneumonitis cases had DAD patterns; this is consistent with previous reports of other anti-cancer drugs [11, 15,16,17,18,19]. ILD/pneumonitis cases with DAD patterns often respond poorly to corticosteroid treatment [11], and some of the patients with DAD patterns in this report died even after receiving high-dose corticosteroid treatment immediately after diagnosis. However, in the absence of other effective treatment options, high-dose corticosteroid therapy should be initiated as soon as possible. Careful monitoring, prompt diagnosis, and immediate treatment are important for ILD management [20] and may potentially help prevent poor outcomes of patients with DAD patterns.

In the early phase of clinical trials of T-DXd, ILD/pneumonitis was identified as an important risk; the guidance for managing T-DXd-related ILD/pneumonitis was created with reference to established guidance for ILD/pneumonitis induced by other anti-cancer drugs and was used during the T-DXd clinical trials [1, 3,4,5,6,7,8,9, 21,22,23,24]. However, many of the non-serious ILD/pneumonitis cases did not have a reported outcome by the end of the study and the response of these cases to corticosteroid therapy was not evaluated [13]. Thus, the reversibility of T-DXd-related ILD/pneumonitis and its responsiveness to corticosteroid therapy is not clearly understood. A statement has since been added to the protocol, clarifying that all ILD/pneumonitis events, regardless of severity or seriousness, must be followed until resolution, including after drug discontinuation. Furthermore, evaluation of the AE outcomes in the T-DXd clinical trials was at the investigator’s discretion. Therefore, in the post-marketing setting, the ILD-AC and the study sponsor established definitions of T-DXd-related ILD/pneumonitis outcomes so that the committee could evaluate outcomes consistently. Cases were followed until the case was considered either recovered or recovered with sequelae, or for up to 12 months after the onset of ILD/pneumonitis. For the cases whose outcome was recovering (n = 37) or not recovered (n = 19), the final outcome will be followed up, and a better outcome can be expected for some cases.

The approved labels for T-DXd include warnings regarding ILD/pneumonitis and guidance for its management, suggesting the use of corticosteroids [25,26,27]. To our knowledge, there has been no published report regarding the effectiveness of corticosteroids for treating T-DXd-related ILD/pneumonitis. A non-clinical report suggests T-DXd-related ILD/pneumonitis is caused by lung inflammation [28]. Therefore, treatment of ILD/pneumonitis involves suppression of inflammation and prevention of irreversible fibrosis [29]. The timing of corticosteroids influences their effectiveness; treatment is considered to be most effective when administered soon after onset, during the inflammatory phase of the condition [30]. High-dose corticosteroid treatment has a strong anti-inflammatory effect that is induced by non-genomic mechanisms [31], and is recommended for severe drug-induced ILD/pneumonitis [11, 20]. In this report, most (83.1%) of the cases evaluated for response to corticosteroids were considered responsive. However, in 5 of 11 fatal cases, patients rapidly deteriorated and died despite immediate administration of high-dose corticosteroids. Rapid deterioration can be difficult to identify in cases with faint shadows on imaging scans, but immediate treatment with high-dose corticosteroids is recommended if bilateral diffuse opacities, dyspnea, or a significant decrease in oxygen saturation from baseline occurs [20]. Other studies of fatal ILD/pneumonitis cases have shown the importance of following the current ILD/pneumonitis guidance [20, 32,33,34]. Our findings show that T-DXd-induced ILD/pneumonitis can progress rapidly and reiterate the importance of careful monitoring of patients receiving T-DXd to provide prompt treatment of severe (grades 3 and above) ILD/pneumonitis cases.

In Japan, rechallenge with T-DXd was not permitted for patients who experienced any grades of ILD/pneumonitis during the period of this surveillance; therefore, the safety of rechallenge with T-DXd treatment was not evaluated in this report. However, as of November 2022, T-DXd rechallenge after complete resolution of grade 1 ILD/pneumonitis was allowed. The safety of resuming treatment with T-DXd in these patients will need to be assessed in the future.

We acknowledge the limitations of this report: this was an ad hoc exploratory analysis. Corticosteroid use (such as duration and route of administration) may be inconsistently recorded on clinical report forms. Future studies on the association between corticosteroid therapy and T-DXd-related ILD/pneumonitis outcomes are needed. Additionally, the evaluated data and cases with an earlier onset of ILD/pneumonitis were considered to have a bias toward serious ILD/pneumonitis cases for two reasons: 1) serious ILD/pneumonitis cases were prioritized for sending to the ILD-AC, and 2) cases that had an earlier onset of ILD/pneumonitis were ready for adjudication before those with late onset. Therefore, our findings may not be representative of all T-DXd-related ILD/pneumonitis cases in Japan and should be carefully interpreted. The incidence of T-DXd-related ILD/pneumonitis cases by severity grade and the time to ILD/pneumonitis onset will be summarized and reported when the adjudication of all potential ILD/pneumonitis cases is completed.

In conclusion, this report is the first to evaluate the adjudicated T-DXd-related ILD/pneumonitis cases in a Japanese post-marketing environment. The relationship between imaging pattern type and ILD/pneumonitis severity was consistent with previous reports, suggesting that cases with DAD patterns have poor outcomes. Evaluating a larger real-world dataset may further identify predictors of clinical outcome.