This expanded-access study evaluated the safety of T-DXd in 64 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma. Our study provided the opportunity for these patients to access T-DXd treatment prior to marketing approval in Japan.

The EAP system in Japan was established by the Japanese MHLW in 2016 [21, 22]; thus, there are relatively fewer examples of its use in Japan than in Europe and the USA [20]. The Japanese EAP system requires careful consideration of the disease stage, severity, and the drug’s potential for complications to ensure the safety of treated patients. Furthermore, expanded-access studies can only be conducted at institutions participating in the main trial and with sufficient prior experience with the study drug and any potential adverse reactions [22]. These studies are intended to both maximize the potential benefits for patients and bridge the gap between clinical trials and post-approval availability. In this expanded-access study, sites that overlapped with those in the DG-01 trial were selected to shorten the time to study initiation as much as possible, while also streamlining the design and taking regional characteristics into consideration. With the cooperation of the medical institutions and other relevant vendors, the expanded-access study was initiated rapidly, providing patients with the opportunity to receive T-DXd for at least 6 months before the drug was approved.

The Japanese MHLW requires that expanded-access studies follow a similar protocol to the corresponding clinical trial, while not interfering with the conduct of the clinical trial, and that the expanded-access study prioritize the safety of the patients [22]. Thus, it was equally important to give due consideration to ensuring patient safety, and also to ensure that the development of T-DXd in the related phase II DG-01 clinical trial was not adversely affected. Considering the limited evidence for the efficacy and safety of T-DXd for the treatment of previously treated HER2-positive advanced gastric cancer patients when this expanded-access study was initiated, this expanded-access study was conducted with most of the same eligibility criteria set in the phase II DG-01 trial regarding bone marrow, renal, hepatic, cardiac function, and performance status [18]. However, some of the eligibility criteria were modified in this expanded-access study: for example, patients without measurable lesions, and patients with confirmed progression on both irinotecan and paclitaxel were included. Furthermore, HER2 status in this expanded-access study could be determined from diagnostic results obtained from local laboratories at each hospital, whereas the DG-01 trial stipulated that HER2 status must be assessed by a central laboratory. The patient characteristics between the DG-01 trial and this expanded-access study were similar in terms of age and sex; however, the population in the expanded-access study included more patients who had received a greater number of previous cancer treatments than the DG-01 trial population [18]. In addition, our expanded-access study allowed patients who were assigned to the physician’s choice arm in the DG-01 trial; two patients from the physician’s choice cohort received T-DXd in this expanded-access study. These patients had the option to continue treatment at the end of the expanded-access study and following marketing approval. Thus, our expanded-access study provided T-DXd to patients who did not receive T-DXd in the phase II DG-01 trial and enabled patients to benefit from the continued T-DXd treatment. Most patients who discontinued treatment received the commercial drug of their own choice after this expanded-access study ended, thereby bridging the gap between clinical trials and post-approval availability.

The AEs reported in this expanded-access study were generally manageable and tolerable. As the dose was reduced in 27/64 patients (42.2%), physicians should modify the dose of T-DXd according to the patient’s condition and tolerability to mitigate AEs. It must be noted that the DG-01 trial and this expanded-access study were different in terms of treatment duration and data collection, which precludes direct comparisons. The median duration of T-DXd treatment in this expanded-access study was 2.7 months (range, 0.7–6.2), which is shorter compared with the DG-01 trial [18]; this may partly explain the discrepancy in the observed SAE frequencies between this study and the DG-01 trial (26.6% and 44.0%, respectively). In addition, the observed frequencies of drug-related SAEs in this expanded-access study and the DG-01 were 15.6% and 21.6%, respectively [18]. The reason for the difference in treatment duration is that this expanded-access study was conducted for only a short period until marketing approval in Japan. Furthermore, the data included many patients who had received fewer T-DXd administrations, including patients receiving only one administration just before the end of this expanded-access study. A comparison of SAEs with T-DXd treatment is challenging as SAE frequencies vary between trials, even among trials of patients with the same type of cancer [18, 23,24,25,26,27,28]. Thus, it is difficult to reach any conclusions regarding differences in SAE frequency between this expanded-access study and other T-DXd clinical trials because of differences in T-DXd dose, treatment line, treatment duration, and cancer type [18, 23,24,25,26,27,28]. However, the results of this expanded-access study are generally consistent with the safety results as identifying recommended dose in HER2-positive gastric cancer [29]. In addition, the observed safety profile of T-DXd in this expanded-access study was similar to the profile observed in previous clinical trials regarding AE type and severity; no new safety concerns were identified despite the relatively short study duration.

We acknowledge the limitations of the expanded-access study. In accordance with the Japanese guidelines for EAPs [21], the primary focus of this expanded-access study was to provide patients with access to T-DXd, and we did not comprehensively evaluate the safety or efficacy of T-DXd. Therefore, there were no biomarker assessments, including microsatellite instability assessments, circulating tumor DNA, and HER2 amplification detection, and not all AEs and clinical outcomes were reported on the CRFs. AEs outside of the scope of interest for the expanded-access study were not included on the CRFs; therefore, not all AEs were reported. Only SAEs, all potential cases of ILD/pneumonitis, all liver-related events, and all cases of overdose were reported. In addition, during the study period, the number of patients with progressive disease as assessed by a physician was 19/64 (29.7%), but the limited duration prior to study termination and the limited data provided in the CRFs (such as presence or absence of measured lesions) precluded any further inferences regarding clinical effectiveness.

In conclusion, this expanded-access study provided T-DXd to patients with locally advanced or metastatic HER2-positive gastric and GEJ adenocarcinoma prior to marketing approval of T-DXd in Japan. No unexpected SAEs or other significant events were reported, and no new safety concerns were identified.