Trastuzumab deruxtecan as the new standard of care in HER2-low unresectable and/or metastatic breast cancer

Thus far, available HER2-directed therapies were found to be ineffective in patients with HER2-low cancers. DESTINY-Breast04 is the first phase III trial of a HER2-directed therapy, trastuzumab deruxtecan, in patients with HER2-low metastatic breast cancer to show a statistically significant and clinically meaningful benefit in PFS and OS compared to standard-of-care treatment, regardless of HR status, with a generally manageable safety profile.

HER2-low metastatic breast cancer (mBC) is defined by immunohistochemistry (IHC) scores of 1+ or 2+/ISH-. These “HER2-low” tumours represent a heterogeneous population with a high prevalence of hormone receptor (HR) coexpression and without distinct biology. HER2-low mBC is often treated as HER2-negative mBC, with limited options for later lines of treatment. Current HER2-targeted therapies are not effective for patients with tumours that express lower levels of HER2, highlighting the need for more effective drugs. Trastuzumab deruxtecan (T-DXd) is a next-generation antibody–drug conjugate consisting of a humanised anti-HER2 monoclonal antibody linked to a topoisomerase I inhibitor payload through a tetrapeptide-based cleavable linker. Results from a phase Ib study have reported promising efficacy in heavily pre-treated patients with HER2-low mBC. Therefore, the phase III DESTINY-Breast04 was set up to evaluate the efficacy and safety of T-DXd as compared with the physician’s choice of chemotherapy (TPC) in patients with HER2-low metastatic breast cancer.

Study Design

In DESTINY‐Breast04, 557 patients with centrally confirmed HER2-low mBC who were previously treated with 1-2 prior lines of chemotherapy in the metastatic setting were randomly assigned (2:1) to T-DXd 5.4 mg/kg or TPC (capecitabine, eribulin, gemcitabine, paclitaxel, or nab-paclitaxel). The primary endpoint was progression-free survival (PFS) determined by blinded independent central review (BICR) in patients with HR+ mBC. Key secondary endpoints (hierarchically tested after the primary endpoint) include PFS by BICR in the full analysis set (FAS; HR+/−) and overall survival (OS) in patients with HR+ mBC and in the FAS. Other endpoints were objective response rate, duration of response, safety, and an exploratory analysis of patients with HR− mBC.

Results

Of the 557 patients randomised, 499 (89.6%) had HR+ disease, and 58 (10.4%) had HR- disease. Patients received a median of 3 prior lines of systemic therapy in the metastatic setting. After a median follow-up of 18.4 months, the primary endpoint, PFS, in patients with cancers that were HER2-low and hormone receptor positive (HR+), was nearly double for T-DXd vs. standard chemotherapy (10.1 vs. 5.4 months, HR[95%CI]: 0.51[0.40-0.64], p< 0.0001). Highly similar results were observed in the full analysis set (9.9 vs. 5.1 months, HR[95%CI]: 0.50[0.40-0.63], p< 0.0001). The secondary endpoint of OS was also significantly better in the HER2-low, HR+ subgroup of patients (23.9 vs. 17.5 months, HR[95%CI]: 0.64[0.48-0.86], p= 0.0028) and in all patients who received T-DXd compared to standard therapy (23.4 vs. 16.8 months, HR[95%CI]: 0.64[0.49-0.84], p= 0.0010). Subgroup analyses showed consistent benefit for T-DXd among all patient subgroups, including IHC status, prior use of CDK4/6 inhibitors and lines of chemotherapy. The median PFS in the HR- cohort was 8.5 months in the T-DXd group and 2.9 months in the physician’s choice group (HR[95%CI]: 0.46[0.24-0.89]). Median overall survival in this population was respectively 18.2 months and 8.3 months (HR[95%CI]: 0.48[0.24-0.95]).

The percentage of patients with a confirmed objective response in the HR+ cohort was 52.6% in the T-DXd group and 16.3% in the TPC group. The corresponding percentages in the HR- cohort were 50.0% and 16.7%. A total of 12 patients (3.6%) in the HR+ T-DXd group and 1 patient (0.6%) in the TPC group had a complete response; 26 patients (7.8%) and 35 patients (21.1%) in the respective groups had progressive disease as the best overall response. The median treatment duration was 8.2 months for T-DXd and 3.5 months for TPC. Treatment-related adverse events were consistent with previous clinical trials with T-DXd and no new safety concerns were identified. Adverse events of grade 3 or higher occurred in 52.6% of the patients who received T-DXd and 67.4% of those who received the physician's choice of chemotherapy. Adjudicated, drug-related interstitial lung disease or pneumonitis occurred in 12.1% of the patients who received trastuzumab deruxtecan; 0.8% had grade 5 events. There were no concerning cardiac issues.

Conclusion

T-DXd is the first HER2-targeted therapy to demonstrate unprecedented statistically significant and clinically meaningful improvements in PFS and OS as compared to treatment of physician’s choice. A similar magnitude of benefit was observed across all subgroups, including HER2 IHC status and prior use of CDK4/6 inhibitors. The safety of T-DXd is consistent with the known safety profile and showed an overall positive benefit-risk. As such, DESTINY-Breast04 establishes HER2-low (IHC1+, IHC2+/ISH-) metastatic breast cancer as a new targetable patient population, with T-DXd as a new standard of care.

Reference

Modi S, et al. Trastuzumab deruxtecan (T‐DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2‐low unresectable and/or metastatic breast cancer (mBC): Results of DESTINY‐ Breast04, a randomized, phase 3 study. Presented at ASCO 2022; Abstract LBA3.