Sacituzumab govitecan (IMMU-132) was well tolerated and demonstrated early and durable responses in heavily pretreated patients with metastatic triple-negative breast cancer (mTNBC), according to the results of a recent phase I/II study published in the <em>Journal of Clinical Oncology</em>.<br />
Aditya Bardia, MD
Sacituzumab govitecan (IMMU-132) was well tolerated and demonstrated early and durable responses in heavily pretreated patients with metastatic triple-negative breast cancer (mTNBC), according to the results of a recent phase I/II study published in theJournal of Clinical Oncology.
Sacituzumab govitecan is an antibodydrug conjugate that targets Trop-2, which is expressed in more than 90% of TNBCs, by selectively delivering SN-38, the active metabolite of irinotecan. It was granted a breakthrough therapy designation by the FDA in February 2016 for the treatment of patients with mTNBC, following at least 2 treatments for metastatic disease.
In a phase I dose-finding trial in advanced solid tumors, including mTNBC, sacituzumab govitecan showed encouraging therapeutic activity without the preselection of patients for Trop-2 expression in their tumors. The phase II portion of the study expanded accrual in select cancers.
In the analysis of patients with relapsed/refractory mTNBC from the phase I/II single-arm, multicenter basket trial, Aditya Bardia, MD, et al evaluated sacituzumab govitecan in 69 patients who had received at least 1 prior therapy since diagnosis. Most of the patients had extensive metastatic disease and were heavily pretreated, with a median of 5 prior therapies (range, 1-12). The study comprised all patients from the phase II portion of the dose-finding trial as well as 1 patient from the phase I portion who received sacituzumab govitecan at the 10 mg/kg dose, which was the dose selected for development. The primary endpoints of the study were safety and objective response rate (ORR). Secondary endpoints were progression-free survival (PFS) and overall survival (OS).
Patients enrolled in the phase II portion of the trial received a starting dose of 10 mg/kg on days 1 and 8 of a 21-day cycle. The ORR (including 1 patient from the phase I portion) was 30%, with a median response duration of 8.9 months (95% CI, 6.1-11.3). The median PFS was 6.0 months (95% CI, 5.0-7.3), and median OS was 16.6 months (95% CI, 11.1-20.6). The responses had a median onset of 1.9 months.
Of the 69 patients, 3 withdrew as a result of early progression after receiving only 1 or 2 doses without a post-baseline computed tomography assessment, but they were included in the intention-to-treat analysis.
In the intent-to-treat population, 2 patients achieved a complete response (CR) and an additional 19 patients achieved a partial response (PR). The clinical benefit rate (CR + PR + stable disease lasting ≥6 months) was 46% (95% CI, 34%-59%).
One or more grade ≥3 adverse events (AEs) occurred in 41% of patients, including neutropenia (39%), leukopenia (16%), anemia (14%), diarrhea (13%), and vomiting (10%). The incidence of febrile neutropenia was 7%. Grade 3 thrombocytopenia occurred in 2 patients (3%). Three patients discontinued AEs after 6 to 7 doses (grade 3 rash/mucositis, grade 3 transient infusion reaction, grade 2 fatigue after 6 doses). No therapy-related deaths occurred.
Dose reductions occurred in 13 patients (19%), primarily as a result of neutropenia, in the first 2 cycles (either dose 2 or 3), with an additional 11 (16%) requiring later dose reductions. No neutralizing antibodies to the ADC SN-38 or to the antibody were detected, including after the administration of multiple therapy cycles.
In the study, the majority of archival tumor specimens (88%) were moderately to strongly positive for Trop-2 expression by immunohistochemistry. Trop-2 is a 46-kD glycoprotein initially identified in a trophoblast cancer cell line and is overexpressed in many epithelial cancers. It plays a multifunctional cellular role, including transducing of cytoplasmic Ca2+that depends on a specific protein kinase C phosphorylation site. The overexpression of Trop-2 correlates with a poor prognosis in several cancers, including breast cancer.
Irinotecan has shown activity in solid tumors, including metastatic breast cancer, however, it is not well tolerated, with one-third of patients experiencing grade 3/4 diarrhea. In contrast, sacituzumab govitecan can deliver higher levels of SN-38 to tumors with an improved therapeutic index.
As of data cut-off on August 2, 2016, with a median follow-up of 16.6 months, 62 patients had discontinued treatment and 7 were still receiving therapy. Patients received a median of 14 doses (range, 1-67), with a median duration of exposure of 5.3 months (range, 0.2-23.1).
Bardia A, Mayer IA, Diamond JR, et al. Efficacy and Safety of Anti-Trop-2 Antibody Drug Conjugate Sacituzumab Govitecan (IMMU-132) in Heavily Pretreated Patients With Metastatic Triple-Negative Breast Cancer.J Clin Oncol. 2017; 35(19):2141-2148. doi:10.1200/JCO.2016.70.8297