Datopotamab deruxtecan superior to chemotherapy in patients with endocrine resistant HR+/HER2- advanced breast cancer

Results of the TROPION-Breast01 study, presented at SABCS 2023, show that datopotamab deruxtecan (Dato-DXd) improves outcomes compared to chemotherapy in patients with previously treated, inoperable or metastatic, hormone receptor (HR)-positive, HER2-negative breast cancer. Dato-DXd significantly prolonged the progression-free survival (PFS) regardless of the duration of prior CDK4/6 inhibitor treatment and irrespective of the presence of brain metastases. Furthermore, Dato-DXd was well tolerated and significantly delayed the time to subsequent therapy and the time to a deterioration in the quality of life of patients.

Background

Chemotherapy is widely used in the management of patients with endocrine-resistant HR+/HER2– metastatic breast cancer. However, (single-agent) chemotherapy is often associated with a low response rate, a poor prognosis, and significant toxicity including myelosuppression and peripheral neuropathy. Datopotamab deruxtecan (Dato-DXd) is a TROP2-directed antibody-drug conjugate, that selectively delivers a potent Topo-I inhibitor payload directly into tumor cell. Earlier this year, primary results from the phase 3 TROPION-Breast01 study, presented at ESMO 2023, demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) with Dato-DXd compared to investigator’s choice of chemotherapy (ICC) (HR[95%CI]: 0.63[0.52‒0.76]); p< 0.0001). During SABCS 2023, additional efficacy, safety and quality of life data were presented for TROPION-Breast01.

Study design

TROPION-Breast01 enrolled patients aged ≥18 years who had inoperable or metastatic HR+/HER2‒ breast cancer who were previously treated with 1‒2 prior lines of systemic chemotherapy (CT). Patients also had to have disease progression on endocrine therapy (ET) or had to be unsuitable for ET. Patients were randomized (1:1) to Dato-DXd (6 mg/kg q3w) or ICC (eribulin, vinorelbine, capecitabine, or gemcitabine) until progression or unacceptable toxicity. The dual primary endpoints of the study were PFS by blinded independent central review (BICR) per RECIST 1.1, and overall survival (OS). Secondary study objectives included the objective response rate (ORR), the investigator-assessed PFS, the time to the first subsequent therapy (TFST), safety and patient reported outcomes (PROs).

Results

The median investigator-assessed PFS for patients treated with Dato-DXd was 6.9 months, which was significantly longer than the 4.5 median PFS seen with ICC (HR[95%CI]: 0.64[0.53-0.76]; p< 0.0001). At the 12-month landmark, this translated into a PFS rate of 21.7% for Dato-DXd vs. 9.9% with ICC. Also the median TFST was significantly longer with Dato-DXd than with ICC at 8.2 and 5.0 months, respectively (HR[95%CI]: 0.53[0.45-0.64). Interestingly, the benefit in PFS per BICR obtained with Dato-DXd vs. ICC was similar in patients with a prior CDK4/6 inhibitor treatment duration of ≤12 and ≥12 months (HR: 0.61 for both). Dato-DXd also provided a PFS benefit over ICC in patients with brain metastases at baseline (clinically inactive) with a median PFS of 5.6 and 4.4 months, respectively (HR[95%CI]: 0.73[0.39-1.42]).

In terms of safety, Dato-DXd came with a lower rate of grade ≥3 treatment-related adverse events (TRAEs) than ICC at 21% and 45%, respectively. The rate of TRAE-related treatment discontinuation was similar in both arms at 3%. There were no TRAE-related deaths with Dato-DXd (one with ICC: febrile neutropenia). The incidence of grade ≥3 neutropenia was 1% with Dato-DXd as compared to 31% with ICC. In contrast, Dato-DXd did come with a higher incidence of treatment-related stomatitis than ICC (50% vs. 13%, grade ≥3: 6% vs. 3%). Finally, the median time to a deterioration in quality of life was significantly longer for patients treated with Dato-DXd than with ICC at 9.0 and 4.8 months, respectively (HR[95%CI]: 0.76[0.58-0.98]).

Conclusions

TROPION-Breast01 met its primary endpoint, demonstrating a statistically significant and clinically meaningful improvement in PFS (by BICR) with Dato-DXd compared to ICC. This PFS improvement was observed irrespective of prior CDK4/6 inhibitor treatment duration, or the presence of brain metastases. Overall, Dato-DXd demonstrated a more favorable safety profile than ICC, with fewer grade ≥3 TRAEs and fewer dose interruptions, or reductions than ICC. Finally, also the deterioration in quality of life was delayed in the Dato-DXd arm compared to ICC. As such, these results support Dato-DXd as a potential new therapeutic option for patients with endocrine-resistant metastatic HR+/HER2– breast cancer.

Reference

Bardia A, et al. Randomized phase 3 study of datopotamab deruxtecan vs chemotherapy for patients with previously-treated inoperable or metastatic hormone receptor-positive, HER2-negative breast cancer: Results from TROPION-Breast01. Presented at SABCS 2023; Abstract GS02-01.