Efficacy and Safety of Anti-Trop-2 Antibody Drug Conjugate Sacituzumab Govitecan (IMMU-132) in Heavily Pretreated Patients With Metastatic Triple-Negative Breast Cancer

Abstract

Purpose Trop-2, expressed in most triple-negative breast cancers (TNBCs), may be a potential target for antibody-drug conjugates. Sacituzumab govitecan, an antibody-drug conjugate, targets Trop-2 for the selective delivery of SN-38, the active metabolite of irinotecan. Patients and Methods We evaluated sacituzumab govitecan in a single-arm, multicenter trial in patients with relapsed/refractory metastatic TNBC who received a 10 mg/kg starting dose on days 1 and 8 of 21-day repeated cycles. The primary end points were safety and objective response rate; secondary end points were progression-free survival and overall survival. Results In 69 patients who received a median of five prior therapies (range, one to 12) since diagnosis, the confirmed objective response rate was 30% (partial response, n = 19; complete response, n = 2), the median response duration was 8.9 (95% CI, 6.1 to 11.3) months, and the clinical benefit rate (complete response + partial response + stable disease ≥ 6 months) was 46%. These responses occurred early, with a median onset of 1.9 months. Median progression-free survival was 6.0 (95% CI, 5.0 to 7.3) months, and median overall survival was 16.6 (95% CI, 11.1 to 20.6) months. Grade ≥ 3 adverse events included neutropenia (39%), leukopenia (16%), anemia (14%), and diarrhea (13%); the incidence of febrile neutropenia was 7%. The majority of archival tumor specimens (88%) were moderately to strongly positive for Trop-2 by immunohistochemistry. No neutralizing antibodies to the ADC or antibody were detected, despite repeated cycles developed. Conclusion Sacituzumab govitecan was well tolerated and induced early and durable responses in heavily pretreated patients with metastatic TNBC. As a therapeutic target and predictive biomarker, Trop-2 warrants further research.

Sacituzumab govitecan (IMMU‐132), an anti‐Trop‐2‐SN‐38 antibody‐drug conjugate for the treatment of diverse epithelial cancers: Safety and pharmacokinetics

“…29 Trop-2 expression in archived tissues was examined in 150 patients; however, because nearly all specimens were positive, it is not possible to conclude that the prescreening of archived tissue would sufficiently enrich patient selection. It is important to note that safety and efficacy assessments were performed in a diverse population of patients with metastatic cancers who had received multiple and varied prior treatment regimens, including about 30% who received a topoisomerase I inhibitor (primarily patients with gastrointestinal and small cell lung cancer who received an irinotecan-containing regimen or topotecan).…”

“…29,[33][34][35] Sacituzumab govitecan has an excellent PK profile with a low fraction of SN-38G, resulting in lower rates of diarrhea and a manageable toxicity profile. 29,[33][34][35] Sacituzumab govitecan has an excellent PK profile with a low fraction of SN-38G, resulting in lower rates of diarrhea and a manageable toxicity profile.…”

Photoimmunotherapy targeting biliary‐pancreatic cancer with humanized anti‐TROP2 antibody

“…This ADC has the humanized anti‐TROP2 mAb conjugated to a toxic payload, SN‐38 (7‐ethyl‐10‐hydroxycamptothecin, the active metabolite of irinitecan). SN‐38 is a type I topoisomerase inhibitor that causes double‐stranded DNA breaks and apoptosis, which has been reported to be active in patients with advanced, metastatic triple‐negative breast cancer (mTNBC) and metastatic nonsmall‐cell lung cancer (mNSCLC) . In general, ADC treatment has undesired side effects caused by the expression of the target antigen on normal tissue.…”

“…SN-38 is a type I topoisomerase inhibitor that causes double-stranded DNA breaks and apoptosis, which has been reported to be active in patients with advanced, metastatic triple-negative breast cancer (mTNBC) and metastatic nonsmall-cell lung cancer (mNSCLC). 27,28 In general, ADC treatment has undesired side effects caused by the expression of the target antigen on normal tissue. In those trials, sacituzumab govitecan was well tolerated as well as in animal models, 29 and it was suggested that TROP2 may be poorly accessible in normal tissues.…”

Single peptides and combination modalities for triple negative breast cancer

“…This novel ADC (also known as IMMU‐132) can bind to LIV‐1 expressing cancer cells and release the cell‐killing agent (monomethyl auristatin E) into target cells upon internalization (Sussman et al, ). A combination of PARP inhibitors (talazoparib or olaparib) and SGN‐LIV1A exhibits strong antitumor effects and also reduces the growth of tumor in mice models of TNBC (with BRCA1/2 mutation; Bardia et al, ; Moscetti et al, ).…”