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

Abstract

Background: Sacituzumab govitecan (SG), a trophoblast cell surface antigen-2 (Trop-2)-directed antibody-drug conjugate, has demonstrated antitumor efficacy and acceptable tolerability in a phase I/II multicenter trial (NCT01631552) in patients with advanced epithelial cancers. This report summarizes the safety data from the overall safety population (OSP) and efficacy data, including additional disease cohorts not published previously. Patients and methods: Patients with refractory metastatic epithelial cancers received intravenous SG (8, 10, 12, or 18 mg/kg) on days 1 and 8 of 21-day cycles until disease progression or unacceptable toxicity. Endpoints for the OSP included safety and pharmacokinetic parameters with investigator-evaluated objective response rate (ORR per RECIST 1.1), duration of response, clinical benefit rate, progression-free survival, and overall survival evaluated for cohorts (n > 10 patients) of small-cell lung, colorectal, esophageal, endometrial, pancreatic ductal adenocarcinoma, and castrate-resistant prostate cancer. Results: In the OSP (n ¼ 495, median age 61 years, 68% female; UGT1A1*28 homozygous, n ¼ 46; 9.3%), 41 (8.3%) permanently discontinued treatment due to adverse events (AEs). Most common treatment-related AEs were nausea (62.6%), diarrhea (56.2%), fatigue (48.3%), alopecia (40.4%), and neutropenia (57.8%). Most common treatment-related serious AEs (n ¼ 75; 15.2%) were febrile neutropenia (4.0%) and diarrhea (2.8%). Grade !3 neutropenia and febrile neutropenia occurred in 42.4% and 5.3% of patients, respectively. Neutropenia (all grades) was numerically more frequent in UGT1A1*28 homozygotes (28/46; 60.9%) than heterozygotes (69/180; 38.3%) or UGT1A1*1 wild type (59/177; 33.3%). There was one treatment-related death due to an AE of aspiration pneumonia. Partial responses were seen in endometrial cancer (4/18, 22.2% ORR) and small-cell lung cancer (11/62, 17.7% ORR), and one castrate-resistant prostate cancer patient had a complete response (n ¼ 1/11; 9.1% ORR). Conclusions: SG demonstrated a toxicity profile consistent with previous published reports. Efficacy was seen in several cancer cohorts, which validates Trop-2 as a broad target in solid tumors.

Trop2 Expression in Extramammary Paget’s Disease and Normal Skin

“…Our immunohistochemical results revealed strong Trop2 expression in EMPD, suggesting EMPD is a good candidate for sacituzumab govitecan. Furthermore, strong Trop2 expression in hair follicles accords well with the fact that alopecia was a common (occurred in 40.4% of patients) treatmentrelated adverse event in the basket trial [36].…”

“…As a Trop2-targeted therapy, sacituzumab govitecan has recently entered clinical use [ 35 , 36 ]. Sacituzumab govitecan is an ADC consisting of a fully humanized IgG1 anti-Trop2 antibody and the active metabolite of irinotecan (SN-38), a topoisomerase I inhibitor.…”

“…In the randomized trial, both progression-free survival and overall survival were significantly longer with the addition of sacituzumab govitecan than with single-agent chemotherapy [ 35 ]. In a phase I/II basket trial (NCT01631552), sacituzumab govitecan also demonstrated antitumor efficacy and acceptable tolerability in patients with miscellaneous advanced epithelial cancers (e.g., small-cell lung cancer, colorectal cancer, esophageal cancer, endometrial cancer, pancreatic ductal adenocarcinoma, prostate cancer) [ 36 ]. In the trial, patients were enrolled regardless of their Trop2 expression levels, and Trop2 was validated as a broad target in solid tumors.…”

“…In studies of breast and lung cancers, Trop2 inhibition exerted anticancer effects [ 30 , 31 ]. Recently, an antibody–drug conjugate (ADC) targeting Trop2 was used in clinical trials in lung, urothelial, breast, and other miscellaneous epithelial cancers, and clinical benefits were observed [ 32 , 33 , 34 , 35 , 36 ]. However, little is known about the role of Trop2 in EMPD.…”

Linker Design Impacts Antibody-Drug Conjugate Pharmacokinetics and Efficacy via Modulating the Stability and Payload Release Efficiency

“…Ideally, the linker that connects the antibody to the drug should be stable in circulation and cleaved enzymatically (by a protease such as cathepsin B) or chemically (by reducing agents such as cysteine and GSH) inside the cell to release the attached payload to act on the intended target ( Zhang et al, 2016a ; Zhang et al, 2016b ; Ponziani et al, 2020 ; Poreba, 2020 ) In the absence of linker stability in serum, premature release of the payload can result in systemic toxicity. Whereas the low stability of Trodelvy ® bearing an unstable linker seems to avoid this effect with manageable safety likely due to the selected toxicity profile of its topisomerase I inhibitor payload ( Bardia et al, 2017 ; Sahota and Vahdat, 2017 ; Bardia et al, 2021 ). On the other hand, inefficient cleavage of the linker inside the cell may not produce the intended antitumor activity ( Zhang et al, 2016a ; Zhang et al, 2016b ; Ma et al, 2016 ; Poreba, 2020 ).…”