Efficacy of administration sequence: Sacituzumab Govitecan and Trastuzumab Deruxtecan in HER2-low metastatic breast cancer

Abstract

Background: Current guidelines recommend that patients with HER2-low metastatic breast cancer (MBC) receive sequentially two antibody-drug conjugates (ADCs): Sacituzumab Govitecan (SG) and Trastuzumab Deruxtecan (T-DXd), despite a similar payload. However, the effectiveness of one after another is unknown.

Methods: ADC-Low is a multicentre, retrospective study evaluating the efficacy of SG and T-DXd, one after another, with or without intermediary lines of chemotherapy, in patients with HER2-low MBC.

Results: One hundred and seventy-nine patients were included: the majority with HR-negative tumours received SG first (ADC1) (n = 100/108) while most with HR-positive tumours received T-DXd first (n = 56/71). Median progression-free survival 2 was short: 2.7 months (95% CI: 2.4-3.3) in the whole population, respectively, 3.1 (95% CI: 2.6-3.6) and 2.2 months (95% CI: 1.9-2.7) for patients receiving T-DXd or SG second (ADC2). Intermediary lines of chemotherapy between ADC1 and ADC2 had no impact. Primary resistance to ADC2 occurred in 54.4% of patients. Certain patients showed initial response to ADC2.

Conclusions: Clinical benefit of sequentially administered SG and T-DXd is limited for most patients. Nevertheless, a subset of patients might benefit-on the short term-from a second ADC. Additional studies are needed to identify patients who could benefit from two ADCs with similar payloads.

Fig. 1. Kaplan–Meier curves of PFS2, PFI1, and subgroups analysis.

a PFS2 in the whole population (dark curve), for T-DXd as ADC2 (blue curve) and for SG as ADC2 (green curve). b PFS2 for patients with HR− tumours receiving T-DXd as ADC2 (blue curve) and for patients with HR+ tumours receiving SG as ADC2 (green curve). c PFS2 according to intermediary lines (red curve) or not (blue curve) between ADC1 and ADC2, regardless of the order of the ADC. d PFI1 for patients with HR− tumours receiving SG as ADC1 (green curve) and for patients with HR+ tumours receiving T-DXd as ADC1 (blue curve).

Fig. 2. Sankey diagram of switch in primary and secondary resistances between ADCs.

Primary resistance defined as patients with progressive disease (PD) as best overall response under ADC; secondary resistance defined as complete response, partial response, or stable disease at first assessment. One patient was not evaluable for response on ADC1 since the ADC1 was stopped prematurely due to toxicity. Thirty-one patients were still receiving ADC2 and had not been evaluated at the time of analysis and were considered as non-evaluable.