Abstract and Introduction
Purpose: Hormone receptor–positive (HR+) human epidermal growth factor receptor 2–negative (HER2–) endocrine-resistant metastatic breast cancer is treated with sequential single-agent chemotherapy with poor outcomes. Sacituzumab govitecan (SG) is a first-in-class antibody-drug conjugate with an SN-38 payload targeting trophoblast cell-surface antigen 2, an epithelial antigen expressed in breast cancer.
Methods: In this global, randomized, phase III study, SG was compared with physician's choice chemotherapy (eribulin, vinorelbine, capecitabine, or gemcitabine) in endocrine-resistant, chemotherapy-treated HR+/HER2– locally recurrent inoperable or metastatic breast cancer. The primary end point was progression-free survival (PFS) by blinded independent central review.
Results: Patients were randomly assigned to receive SG (n = 272) or chemotherapy (n = 271). The median age was 56 years, 95% had visceral metastases, and 99% had a prior cyclin-dependent kinase 4/6 inhibitor, with three median lines of chemotherapy for advanced disease. Primary end point was met with a 34% reduction in risk of progression or death (hazard ratio, 0.66 [95% CI, 0.53 to 0.83; P = .0003]). The median PFS was 5.5 months (95% CI, 4.2 to 7.0) with SG and 4.0 months (95% CI, 3.1 to 4.4) with chemotherapy; the PFS at 6 and 12 months was 46% (95% CI, 39 to 53) v 30% (95% CI, 24 to 37) and 21% (95% CI, 15 to 28) v 7% (95% CI, 3 to 14), respectively. Median overall survival (first planned interim analysis) was not yet mature (hazard ratio, 0.84; P = .14). Key grade ≥ 3 treatment-related adverse events (SG v chemotherapy) were neutropenia (51% v 38%) and diarrhea (9% v 1%).
Conclusion: SG demonstrated statistically significant PFS benefit over chemotherapy, with a manageable safety profile in patients with heavily pretreated, endocrine-resistant HR+/HER2– advanced breast cancer and limited treatment options.
Although endocrine therapy combined with cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) has extended overall survival (OS) for metastatic hormone receptor–positive (HR+) human epidermal growth factor receptor 2–negative (HER2–) breast cancer to over 5 years in the first-line setting[1–5] and combinations with phosphoinositide 3-kinase or mammalian target of rapamycin inhibitors offer benefit in subsequent treatment lines, endocrine resistance eventually develops. Sequential single-agent chemotherapy is the next therapeutic option but is associated with declining response rates and disease control and increased toxicity.[6–10]
Sacituzumab govitecan (SG) is a first-in-class trophoblast cell-surface antigen 2 (Trop-2)–directed antibody-drug conjugate (ADC), consisting of a humanized anti–Trop-2 monoclonal antibody conjugated to the active metabolite of irinotecan, SN-38, via a hydrolyzable CL2A linker. Trop-2 is a transmembrane calcium signal transducer highly expressed in solid tumors, especially HR+/HER2– and triple-negative breast cancers (with a prevalence of > 90%), and linked to tumor progression and poor prognosis.[13–15] Internalization of Trop-2–bound SG delivers SN-38 into the tumor cell through hydrolysis of the linker. Because SN-38 is a membrane-permeable free molecule released in the tumor microenvironment, it may elicit antitumor effects in adjacent non–Trop-2-expressing tumor cells (bystander effect).
SG received full authorization from the Food and Drug Administration and European Medicines Agency for patients with metastatic triple-negative breast cancer who had received at least two prior chemotherapies (at least one for metastatic disease) and has accelerated approval for locally advanced or metastatic urothelial cancer.[17–19] In the phase I/II IMMU-132-01 basket study, SG showed encouraging activity and safety in 54 patients with HR+/HER2– metastatic breast cancer (MBC) who progressed on at least one line of endocrine therapy and at least one prior chemotherapy in the metastatic setting. The objective response rate was 31.5%, and the median progression-free survival (PFS) and OS were 5.5 and 12 months, respectively (CDK4/6i-pretreated group, 25%, 3.8 and 11 months).
Here, we provide the primary results of TROPiCS-02, a global, randomized, open-label, multicenter phase III study of SG versus single-agent chemotherapy in patients with locally recurrent inoperable or metastatic HR+/HER2– breast cancer (Data Supplement, online only).
J Clin Oncol. 2022;40(29):3365-3376. © 2022 American Society of Clinical Oncology