Sacituzumab govitecan in previously treated hormone receptor-positive/HER2-negative metastatic breast cancer: final results from a phase I/II, single-arm, basket trial

Abstract

Background: Trophoblast cell-surface antigen-2 (Trop-2) is expressed in epithelial cancers, including hormone receptorpositive (HRþ) metastatic breast cancer (mBC). Sacituzumab govitecan (SG; Trodelvy®) is an antibodyedrug conjugate composed of a humanized anti-Trop-2 monoclonal antibody coupled to SN-38 at a high drug-to-antibody ratio via a unique hydrolyzable linker that delivers SN-38 intracellularly and in the tumor microenvironment. SG was granted accelerated FDA approval for metastatic triple-negative BC treatment in April 2020. Patients and methods: We analyzed a prespecified subpopulation of patients with HRþ/human epidermal growth factor receptor 2-negative (HER2À) HRþ/HER2À mBC from the phase I/II, single-arm trial (NCT01631552), who received intravenous SG (10 mg/kg) and whose disease progressed on endocrine-based therapy and at least one prior chemotherapy for mBC. End points included objective response rate (ORR; RECIST version 1.1) assessed locally, duration of response (DOR), clinical benefit rate, progression-free survival (PFS), overall survival (OS), and safety. Results: Fifty-four women were enrolled between 13 February 2015 and 1 June 2017. Median (range) age was 54 (33-79) years and all received at least two prior lines of therapy for mBC. At data cut-off (1 March 2019), 12 patients were still alive. Key grade !3 treatment-related toxicities included neutropenia (50.0%), anemia (11.1%), and diarrhea (7.4%). Two patients discontinued treatment due to treatment-related adverse events. No treatment-related deaths occurred. At a median follow-up of 11.5 months, the ORR was 31.5% [95% confidence interval (CI), 19.5%e45.6%; 17 partial responses]; median DOR was 8.7 months (95% CI 3.7e12.7), median PFS was 5.5 months (95% CI 3.6e7.6), and median OS was 12 months (95% CI 9.0e18.2). Conclusions: SG shows encouraging activity in patients with pretreated HRþ/HER2À mBC and a predictable, manageable safety profile. Further evaluation in a randomized phase III trial (TROPiCS-02) is ongoing (NCT03901339). Trial registration: ClinicalTrials.

Sacituzumab govitecan, a Trop-2-directed antibody-drug conjugate, for patients with epithelial cancer: final safety and efficacy results from the phase I/II IMMU-132-01 basket trial

“…Efficacy data for the TNBC, 32 metastatic HRþ/HER2À breast cancer, 38 mUC, 37 SCLC (n ¼ 50), 36 and NSCLC 35 cohorts have been published previously, were confirmed in the March 2019 data cut-off (Table 3), and are not discussed further here.…”

“…IMMU-132-01 was a single-arm, open-label, multicenter phase I/II trial comprising a dose-escalation 31 and a cohortexpansion phase. 32,[35][36][37][38] Eligible patients were >18 years of age with metastatic cancer [cervical, clear-cell renal, CRC, epithelial ovarian, endometrial, esophageal, gastric, hepatocellular, CRPC, pancreatic ductal adenocarcinoma, squamous cell head and neck, thyroid, urothelial (UC) cancer; glioblastoma multiforme; mTNBC or non-mTNBC; and SCLC or NSCLC] who had relapsed after or were refractory to at least one prior standard therapeutic regimen. Study eligibility criteria were described previously 32 and summarized in Supplementary Material, available at https://doi.org/10.…”

“…34 The 10 mg/kg dose was chosen for future development 34 and a later analysis of the overall safety population (OSP) from this study continued to show a consistent and predictable toxicity profile. 32 Data published on multiple histologic cohorts showed SG demonstrated antitumor efficacy in non-small-cell lung cancer (NSCLC, n ¼ 47), 35 small-cell lung cancer (SCLC, n ¼ 50), 36 mUC (n ¼ 45), 37 metastatic hormone receptorpositive/human epidermal growth factor receptor 2negative (HRþ/HER2À) breast cancer (n ¼ 54), 38 and metastatic triple-negative breast cancer (mTNBC, n ¼ 108). 32 In the mTNBC cohort, an objective response rate (ORR) of 33.3% with durable duration of response (DOR; median DOR ¼ 7.7 months) was noted, leading to the accelerated approval of SG for the treatment of adult patients with mTNBC who received at least two prior therapies for metastatic disease.…”

Antibody–drug conjugates in solid tumors: a look into novel targets

“…SG activity has been consequently explored also in this BC subtype and promising results recently emerged from the HR+/HER2−mBC cohort of the IMMU-132-01 basket trial. At a median follow-up of 11.5 months, the ORR was 31.5%, median DOR was 8.7 months, median PFS was 5.5 months, and median OS was 12 months [53]. Even if preliminary, responses and clinical activity here achieved are significant when compared to the alternative standard regimens for heavily pretreated HR+ mBC, in which chemotherapy provides poor benefit.…”

Advances in Therapy for Hormone Receptor (HR)-Positive, Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Advanced Breast Cancer Patients Who Have Experienced Progression After Treatment with CDK4/6 Inhibitors

“…63,64 A Trop-2 directed antibody-drug conjugate sacituzumab govitecan (IMMU-132) has shown benefit in HR+ ABC. 65 This therapeutic agent is a potentially valuable for patients pretreated with CDK4/6 inhibitors. The phase III TROPICS-02 trial is currently investigating this agent.…”