T-DXd yields superior outcomes over chemotherapy-based regimens in HER2-positive metastatic patients previously treated with T-DM1

Results from the phase III DESTINY-Breast02 trial demonstrated that trastuzumab deruxtecan (T-DXd) as compared to capecitabine-based regimens, led to higher response rates and longer survival in the third line setting of patients with HER2-positive metastatic breast cancer who were previously treated with trastuzumab emtansine (T-DM1).

Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate that uses the HER2-targeted antibody trastuzumab to deliver a cytotoxic payload selectively to HER2-expressing cells. In the single-arm, phase II DESTINY-Breast01 trial, T-DXd showed clinical activity in the third-line setting for patients with HER2-positive metastatic breast cancer (mBC) who were previously treated with trastuzumab emtansine (T-DM1), another HER2-targeted antibody-drug conjugate. The open-label, phase III DESTINY-Breast02 trial was designed as a confirmatory study for DESTINY-Breast01 to evaluate T-DXd versus treatment of physician’s choice (TPC) in patients previously treated with T-DM1.

Study design

Patients with HER2+ unresectable or mBC who progressed on or after T-DM1 were randomised 2:1 to receive T-DXd (5.4 mg/kg Q3W) or TPC (trastuzumab + capecitabine or lapatinib + capecitabine) and were stratified by hormone receptor (HR) status (HR+/HR-), prior pertuzumab treatment, and history of visceral disease. The primary endpoint of this time-driven primary analysis was progression-free survival (PFS) as determined by blinded independent central review (BICR). The powered secondary endpoint was overall survival (OS). Other secondary endpoints included confirmed objective response rate (ORR) by BICR, duration of response (DoR) by BICR, PFS by investigator assessment, safety, and others.

Results

In total, 608 patients were randomised to receive T-DXd (N= 406) or TPC (N= 202). Patients receiving T-DXd and TPC had a median age of 54.2 and 54.7 years, respectively, with a median of two prior lines of systemic therapy in the metastatic setting. Median treatment duration was 11.3 months in the T-DXd arm and approximately 4.5 months in the TPC arm.

Among the patients treated with T-DXd, 69.7% experienced an objective response, as compared to 29.2% of patients treated with TPC (p< 0.0001). Complete responses were obtained in respectively 14.0% and 5.0% of patients. Those treated with T-DXd were also 64% less likely to experience disease progression than patients receiving TPC, with a median progression-free survival of 17.8 months and 6.9 months for patients in the T-DXd and TPC arms, respectively (HR[95%CI]: 0.36[0.28-0.45], p< 0.000001). Two-year PFS rates were 42.2% for T-DXd and 13.9% for TPC. Results were consistent across all key subgroups. Overall survival was also significantly longer for patients treated with T-DXd (39.2 vs. 26.5 months, HR[95%CI]: 0.66[0.50-0.86], p= 0.0021). Two-year OS rates were respectively 65.9% and 54.3% for T-DXd and TPC. Median duration of treatment was 19.6 months for T-DXd and 8.3 months for TPC. The overall safety profile was consistent with the established safety of T-DXd, with no new safety signals observed. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 52.7% and 44.1% of patients receiving T-DXd and TPC, respectively. Adjudicated drug-related interstitial lung disease (ILD) occurred in 10.4% of patients with T-DXd vs. 0.5% of patients with TPC. In the T-DXd arm, most ILD cases (88.1%) were grade 1 or 2, although grade 5 ILD was reported in 2 (0.5%) patients.

Conclusion

Results from DESTINY-Breast02 confirmed the clinical benefit and superiority of T-DXd over conventional chemotherapy-based regimens in patients with HER2+ mBC previously treated with T-DM1, as evidenced by significant and clinically meaningful improvements in PFS and OS. These data, together with earlier reported results from the DESTINY-Breast03 study of T-DXd vs. T-DM1 solidify T-DXd as an optimal treatment option in patients with progressive HER2+ mBC across broad settings.

Reference

Krop I, et al. Trastuzumab deruxtecan vs physician’s choice in patients with HER2+ unresectable and/or metastatic breast cancer previously treated with trastuzumab emtansine: primary results of the randomized, phase 3 study DESTINY-Breast02. Presented at SABCS 2022; Abstract GS2-01.