TRASTUZUMAB DERUXTECAN IN PREVIOUSLY TREATED HER2-LOW ADVANCED BREAST CANCER

August 2022 Clinical Practice Ariez

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 manageable safety profile.

HER2-low metastatic breast cancer (mBC) is defined by a score of 1+ on immunohistochemical (IHC) analysis or as an ICH score of 2+ and negative results on in situ hybridisation. These “HER2-low” tumours represent a heterogeneous population with a high prevalence of hormone receptor (HR) co-expression 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 phase I and phase II studies have shown promising results 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 Q3W 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, 331 patients in the trastuzumab deruxtecan group (88.7%) and 163 patients in the TPC group (88.6%), comprised the hormone receptor–positive cohort. The demographic and clinical characteristics of the patients at baseline were similar in the two trial groups and were largely representative of the overall population of patients with HER2-negative breast cancer. Patients received a median of three 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= 0.003) 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= 0.001). 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 duration of response was 10.7 months for T-DXd and 6.8 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; three patients (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, Jacot W, Yamashita T, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022;387:9-20.

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