US Food and Drug Administration Approval Summary: Fam-Trastuzumab Deruxtecan-nxki for Human Epidermal Growth Factor Receptor 2-Low Unresectable or Metastatic Breast Cancer

Abstract

PURPOSE The US Food and Drug Administration approved fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd) for the treatment of adult patients with unresectable or metastatic human epidermal growth factor receptor 2 (HER2)-low (immunohistochemistry 1 + or immunohistochemistry 2+/in situ hybridization–) breast cancer who have received a prior chemotherapy in the metastatic setting or developed disease recurrence during or within 6 months of completing adjuvant chemotherapy. PATIENTS AND METHODS Approval was based on DESTINY-Breast04, a phase III, randomized, open-label, multicenter trial in patients with unresectable or metastatic HER2-low breast cancer, determined at a central laboratory. A total of 557 patients were randomly assigned (2:1) to receive either T-DXd 5.4 mg/kg intravenously once every 3 weeks (n = 373) or physicians' choice of chemotherapy (n = 184). RESULTS The study met its primary efficacy end point of progression-free survival (PFS) by blinded independent central review assessment in the hormone receptor–positive (HR+) cohort (N = 494) with an estimated hazard ratio (HR) of 0.51(95% CI, 0.40 to 0.64; P < .0001). Key secondary end points were also met, including PFS in the intent-to-treat population with an HR of 0.50 (95% CI, 0.40 to 0.63; P < .0001), overall survival (OS) in the HR+ cohort with an HR of 0.64 (95% CI, 0.48 to 0.86; P = .0028) and OS in the intent-to-treat with an HR of 0.64 (95% CI, 0.49 to 0.84; P = .0010). The safety profile of T-DXd was consistent with previously approved indications, and no new safety signals were observed in this study population. CONCLUSION The approval of T-DXd in HER2-low metastatic breast cancer was based on statistically significant and clinically meaningful PFS and OS improvements observed in the DESTINY-Breast04 trial and represents the first approved therapy specifically for the treatment of HER2-low metastatic breast cancer.

Expression of c-erb-B2 oncoprotein as a neoantigen strategy to repurpose anti-neu antibody therapy in a model of melanoma

“…[24][25][26] Importantly, the anti-HER2/neu ADCs have been shown to effective in low HER2-expressing cancers because the chemotherapeutic component of the ADCs exerts its anti-tumor effect after targeted delivery to the HER2 + tumors, even if the HER2 expression is low. 27 Altogether, this results in the bystander effect that is characteristic of ADCs, but not of monoclonal antibodies. 28 Our model aims to take advantage of these currently available therapies and repurposes them for cancers that do not express HER2/neu as a therapeutic biomarker, such as melanoma.…”

Systematic review of recent advancements in antibody-drug and bicycle toxin conjugates for the treatment of urothelial cancer

“…This drug has already received approval for the treatment of HER2-low breast cancer based on the DESTINY-Breast04 trial. 93 The DESTINY-Pantumor-02 trial is investigating this drug for use in multiple solid tumor types, including a cohort for la/mUC that progressed following one or more prior systemic therapies. 94 In the urothelial cancer cohort, 41 patients enrolled.…”

Antibody-Drug Conjugates in Breast Cancer: A Comprehensive Review of How to Selectively Deliver Payloads

“…As of August 5, 2022, the FDA has approved T-DXd for the treatment of unresectable or metastatic HER2-low BC in patients who have previously received chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy, without restrictions for the TNBC patient population. 45 …”

“…As of August 5, 2022, the FDA has approved T-DXd for the treatment of unresectable or metastatic HER2-low BC in patients who have previously received chemotherapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy, without restrictions for the TNBC patient population. 45 Table 1 also presents data from the primary studies published on ADCs in the TNBC context. Recent studies in TNBC have explored the use of novel ADCs in combination with other chemotherapy agents, immunotherapy, PI3K/ AKT/m-TOR inhibitors, and PARP inhibitors, with promising results (Table 3).…”