Dato-DXd Fails to Show OS Benefit in Pretreated HR+/HER2-Low or -Negative Metastatic Breast Cancer

Treatment with datopotamab deruxtecan (dato-DXd) did not significantly improve overall survival (OS) compared with investigator’s choice of chemotherapy in pretreated patients with inoperable or metastatic hormone receptor–positive, HER2-low or -negative breast cancer, according to findings from the final OS analysis of the phase 3 TROPION-Breast01 trial (NCT05104866).¹

Final OS results will be presented at an upcoming medical meeting and submitted to global regulatory agencies reviewing applications for the agent. In April 2024, the FDA accepted a biologics license application seeking the approval of Dato-DXd for the treatment of adult patients with unresectable or metastatic hormone receptor–positive, HER2-negative breast cancer who have received prior systemic therapy for unresectable or metastatic disease, based on prior data from TROPION-Breast01.²

Primary results from TROPION-Breast01 presented at the 2023 ESMO Congress and subsequently published in the Journal of Clinical Oncology showed that at a median follow-up of 10.8 months, Dato-DXd generated a statistically significant and clinically meaningful improvement in progression-free survival (PFS), meeting the study’s co-primary end point. Patients treated with Dato-DXd (n = 365) achieved a median PFS of 6.9 months (95% CI, 5.7-7.4) per blinded independent central review (BICR) assessment vs 4.9 months (95% CI, 4.2-5.5) for those given investigator’s choice of chemotherapy (n = 367), translating to a 37% reduction in the risk of disease progression or death (HR, 0.63; 95% CI, 0.52-0.76; P < .0001).³

Patient-reported outcomes (PROs) were also improved with the agent, according to data presented at the 2024 ASCO Annual Meeting.¹

Regarding safety findings from the final OS analysis, the agent’s toxicity profile was consistent with that observed in prior analyses. Rates of grade 3 or higher treatment-related adverse effects were lower with Dato-DXd compared with chemotherapy. Moreover, the incidence of any-grade interstitial lung disease (ILD) remained low, with no new grade 3 or higher ILD events reported. No new safety signals were observed in the final analysis.

“The metastatic hormone receptor–positive breast cancer treatment landscape has advanced remarkably in the last several years to the benefit of patients,” Susan Galbraith, executive vice president of Oncology Research and Development at AstraZeneca, stated in a news release. “Based on the TROPION-Breast01 results, there is evidence of the clinical value of Dato-DXd in this setting. We will continue discussions with regulatory authorities and apply insights from these results to our clinical development program for Dato-DXd in breast cancer.”

The company notes that subsequent treatment after disease progression or treatment discontinuation may have impacted survival results with Dato-DXd, as multiple antibody-drug conjugates obtained approval during the course of the study.

TROPION-Breast01 Overview

TROPION-Breast01 was a global, open-label, randomized study that enrolled patients with hormone receptor–positive, HER2-low or -negative breast cancer (immunohistochemistry 0, 1+, or 2+/in situ hybridization–) who previously received 1 to 2 lines of chemotherapy in the inoperable/metastatic setting. Patients who experienced disease progression on endocrine therapy or were unsuitable for additional endocrine therapy were allowed to enroll. An ECOG performance status of 0 or 1 was also required.^1,3

Notably, patients were permitted to receive subsequent treatment following disease progression or discontinuation of Dato-DXd or chemotherapy at the discretion of their physician. Crossover between trial arms was not allowed.1

Upon enrollment, patients were randomly assigned 1:1 to receive 6.0 mg/kg of Dato-DXd once every 3 weeks, or investigator’s choice of single-agent chemotherapy.³ The latter arm comprised eribulin at 1.4 mg/m2 on days 1 and 8 of each 3-week cycle; vinorelbine at 25 mg/m2 on days 1 and 8 every 3 weeks; gemcitabine at 1000 mg/m2 on days 1 and 8 of every 3-week cycle; or oral capecitabine at 1000 or 1250 mg/m2 twice per day on days 1 through 14 every 3 weeks.

The study’s primary end points were PFS per RECIST 1.1 criteria assessed by BICR and OS. Key secondary end points included overall response rate, investigator-assessed PFS, and safety.

Ongoing Evaluation of Dato-DXd

In addition to TROPION-Breast01, Dato-DXd is being evaluated in as a monotherapy and in combination with immunotherapy in more than 20 trials across tumor types. Currently, the agent’s global development program encompasses 7 phase 3 trials in lung cancer and 5 in breast cancer. Phase 3 trials for patients with triple-negative or hormone receptor–positive, HER2-negative breast cancers include TROPION-Breast02 (NCT05374512), TROPION-Breast03 (NCT05629585), TROPION-Breast04 (NCT06112379) and TROPION-Breast05 (NCT06103864).¹

“Dato-DXd has previously shown a statistically significant PFS benefit in TROPION-Breast01, a result supported by multiple meaningful secondary measures including PROs,” Ken Takeshita, MD, global head of Research and Development at Daiichi Sankyo, added in the news release. “We are proud to have brought forth a new standard of care for patients with metastatic breast cancer with [fam-trastuzumab deruxtecan-nxki (Enhertu)] and we remain committed to making Dato-DXd another potential option for patients who can benefit.”

References

1. Datopotamab deruxtecan final overall survival results reported in patients with metastatic HR-positive, HER2-low or negative breast cancer in TROPION-Breast01 Phase III trial. News release. AstraZeneca. September 23, 2024. Accessed September 23, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/datopotamab-deruxtecan-final-overall-survival-results-reported-in-patients-with-metastatic-hr-positive-her2-low-or-negative-breast-cancer-in-tropion-breast01-phase-iii-trial.html#!
2. Datopotamab deruxtecan biologics license application accepted in the US for patients with previously treated metastatic HR-positive, HER2-negative breast cancer. News release. AstraZeneca. April 2, 2024. Accessed September 23, 2024. https://www.astrazeneca.com/media-centre/press-releases/2024/fda-accepts-dato-dxd-bla-for-breast-cancer.html
3. Bardia A, Jhaveri K, Im SA, et al. Datopotamab deruxtecan versus chemotherapy in previously treated inoperable/metastatic hormone receptor-positive human epidermal growth factor receptor 2-negative breast cancer: primary results from TROPION-Breast01. J Clin Oncol. Published online September 12, 2024. doi:10.1200/JCO.24.00920