Japanese Approval Sought for Datopotamab Deruxtecan in Pretreated HR+/HER2– Advanced Breast Cancer

A new drug application (NDA) seeking the approval of datopotamab deruxtecan (Dato-DXd) for the treatment of adult patients with hormone receptor (HR)–positive, HER2-negative, unresectable or recurrent breast cancer after prior chemotherapy has been submitted to Japan’s Ministry of Health, Labour, and Welfare (MHLW).¹

The NDA is supported by data from the phase 3 TROPION-Breast01 trial (NCT05104866), which were presented at the 2023 ESMO Congress. Findings showed that patients treated with Dato-DXd (n = 365) achieved a median progression-free survival (PFS) of 6.9 months (95% CI, 5.7-7.4) vs 4.9 months (95% CI, 4.2-5.5) for those treated with investigator’s choice of chemotherapy (n = 367; HR, 0.63; 95% CI, 0.52-0.76; P < .0001). Overall survival (OS) data were not mature at a median follow-up of 9.7 months; however, a trend was observed favoring Dato-DXd (HR, 0.84; 95% CI, 0.62-1.14).²

“Today’s submission for Dato-DXd in Japan is a significant step forward in our goal to create new standards of care globally with our pipeline of DXd antibody-drug conjugates [ADCs],” Wataru Takasaki, PhD, executive officer, head of the R&D Division in Japan, Daiichi Sankyo, stated in a news release.¹ “We will work closely with the Japan Health Authority to bring this TROP2-directed ADC to patients with previously treated HR-positive, HER2-negative metastatic breast cancer."

TROPION-Breast01 was a global, open-label, randomized study that enrolled patients with HR-positive/HER2-negative breast cancer who were previously treated with 1 to 2 lines of chemotherapy in the inoperable or metastatic setting. Patients needed to have experienced disease progression on endocrine therapy or be unsuitable for endocrine therapy. An ECOG performance status of 0 or 1 was also required.²

Patients were randomly assigned 1:1 to receive 6 mg/kg of Dato-DXd once every 3 weeks, or investigator’s choice of chemotherapy, which consisted of eribulin mesylate on days 1 and 8 of every 3-week cycle; vinorelbine on days 1 and 8 of every 3-week cycles; gemcitabine on days 1 and 8 of every 3-week cycle; or capecitabine on days 1 through 14 of every 3-week cycle.

PFS per RECIST v1.1 criteria assessed by blinded independent central review and OS served as the trial’s dual primary end points. Secondary end points included overall response rate (ORR), investigator-assessed PFS, and safety.

Additional data showed that Dato-DXd elicited an ORR of 36.4%, including a complete response rate of 0.5% vs an ORR of 22.9% with investigator’s choice of chemotherapy.

Regarding safety, the rates of any-grade treatment-related adverse effects (TRAEs) were 94% for Dato-DXd and 86% for chemotherapy. The rates of grade 3 or higher TRAEs were 21% and 45%, respectively. TRAEs led to dose reductions in 21% of patients who received Dato-DXd compared with 30% for those given chemotherapy. TRAEs leading to dose interruptions occurred in 12% and 25% of patients, respectively, and TRAEs led to treatment discontinuation in 3% of patients in each arm. A TRAE led to 1 patient death in the chemotherapy arm. The rates of serious TRAEs were 6% for Dato-DXd and 9% for chemotherapy.

The most common any-grade TRAEs occurring in at least 15% of patients included anemia (11% with Dato-DXd vs 20% with chemotherapy), neutropenia (11% vs 42%), dry eye (22% vs 8%), nausea (51% vs 24%), stomatitis (50% vs 13%), vomiting (20% vs 8%), constipation (18% vs 9%), fatigue (24% vs 18%), and alopecia (36% vs 21%).

References

1. Datopotamab deruxtecan new drug application submitted in Japan for patients with previously treated advanced HR positive, HER2 negative breast cancer. News release. Daiichi Sankyo. March 14, 2024. Accessed March 14, 2024. https://www.daiichisankyo.com/files/news/pressrelease/pdf/202403/20240314_E.pdf
2. Bardia A, Jhaveri K, Im SA, et al. Datopotamab deruxtecan (Dato-DXd) vs chemotherapy in previously treated inoperable or metastatic hormone receptor–positive, HER2-negative (HR+/HER2–) breast cancer (BC): primary results from the randomised phase III TROPION-Breast01 trial. Ann Oncol. 2023;34(suppl 2):S1264-S1265. doi:10.1016/j.annonc.2023.10.015