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 = 495, median age 61 years, 68% female; UGT1A1∗28 homozygous, n = 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 = 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 = 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.

Keywords: IMMU-132; SN-38; Trop-2; antibody-drug conjugate; colorectal cancer; endometrial cancer; small-cell lung cancer.

Conflict of interest statement

Disclosure AB has received research support (paid to institution) from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics, Inc., Mersana, Innocrin, and Biotheranostics Inc.; has served as a consultant to Biotheranostics Inc., Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics, Inc., Spectrum Pharma, Taiho, Sanofi, Daiichi Pharma/AstraZeneca, Puma, Philipps, and Eli Lilly; and has received travel support from Biotheranostics Inc., Pfizer, Novartis, Genentech, Merck, Radius Health, Immunomedics, Inc., Spectrum Pharma, Taiho, Sanofi, and Philipps. WM has received research support (paid to institution) from Immunomedics, Inc. EAK is a stockholder of Immunomedics, Inc. JDB has received research support (paid to institution) from AbbVie/Pharmacyclics, Beigene, EMD Serono, Immunomedics, Inc., Symphogen, Pfizer, Taiho, Novartis, Genentech/Roche, Bayer, Lilly/Loxo, Incyte, Boston Biomedical, Macrogenics, and I-Mab Biopharma; has served as a consultant to Ipsen, Clovis, and QED Therapeutics, EMD Serono, Seattle Genetics, Bayer, Celgene, LSK Biopharma, Eisai, AstraZeneca, Five Prime, Armo, AbbVie, Symphogen, Erytech, and Gritstone; participates in a Data Safety Monitoring Board for the Pancreatic Cancer Action Network; and receives compensation from the National Cancer Institute for study sections and work on an Investigational Drug Steering Committee. LV has received research support from Weill Cornell Medicine, serves on advisory boards for Immunomedics, Inc., Berg Pharma, and Seattle Genetics, and has served as a consultant to Osmol Therapeutics. RM has received research support from the Orlando Health UF Health Cancer Center and has received honorarium from Eli Lilly, Pfizer, Genentech, Immunomedics, Inc., Seattle Genetics, and Bristol-Myers Squibb (BMS). ADS has served as a consultant to Puma and Merck, and has received research support from Gilead, Puma, Immunomedics, Inc., Synthon, Boehringer-Ingelheim, Genentech, and Tesaro. KK has received research support from Immunomedics, Inc., Novartis, Incyte, Genentech/Roche, Eli Lilly, Pfizer, Calithera Biosciences, Acetylon, Seattle Genetics, Amgen, Zentalis Pharmaceuticals, and CytomX Therapeutics; has served as a consultant to Immunomedics, Inc., Merck, Seattle Genetics, Pfizer, Novartis, Eisai, Eli Lilly, Amgen, and AstraZeneca. His spouse is currently employed by Grail and was previously employed at Array and Pfizer. JO has served as a consultant to AbbVie, Agendia, AstraZeneca, BMS, Celgene, Eisai, Genentech, Immunomedics, Inc., Jounce Therapeutics, Lilly, Merck, Novartis, Pfizer, Puma, Roche, and Seattle Genetics. JEG has received research support from BMS, Merck, AstraZeneca, Array, Boehringer Ingelheim, and Genentech, and has served as a consultant to BMS, Merck, Inivata, EMD Serono/Merck KGaA, AstraZeneca, Celgene, and Novartis. TK has received travel support from Merck and has received honoraria from Boehringer Ingelheim. JML holds equity interest in Salus Discovery, LLC. He has served as a consultant to Janssen, Sanofi, Astellas, Pfizer, and Immunomedics, Inc. AS has served as a consultant to Sandoz and Bayer and has received speaking honoraria from BMS. DMG reports previous employment by Immunomedics, Inc. and status as company founder; serving as Chairman of the Board and Chief Scientific Officer of Immunomedics, Inc.; and was a stockholder. He is an inventor and co-inventor of patents pertaining to sacituzumab govitecan, with potential royalties from product sales. RMS was previously employed by Immunomedics, Inc., at the time this study was conducted; has served as a consultant to Immunomedics, Inc.; and was a stockholder of Immunomedics, Inc. PM reports previous employment by Immunomedics, Inc., while study was performed and being a stockholder in Immunomedics, Inc. QH was an employee and stock shareholder of Immunomedics, Inc., a subsidiary of Gilead Sciences, Inc. and has received travel support from Advaxis; spouse is an employee and stock shareholder of Merck. WW reports previous employment by Immunomedics, Inc., while study was performed; served as a consultant to Immunomedics, Inc., and was a stockholder in Immunomedics, Inc. TG was an employee and stockholder of Immunomedics, Inc. a subsidiary of Gilead Sciences, Inc. AJO has served in a consulting or advisory role for Immunomedics, Inc., Celgene, Tyme Therapeutics, Array, Merck, BMS, ProStrakan, Novartis, Pfizer, Eli Lilly, and Genentech; has served in Speaker's Bureau for Daiichi Sankyo; and has received travel, accommodations, expenses from Daiichi Sankyo. All other authors have declared no conflicts of interest.

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