Sacituzumab govitecan, a novel, third-generation, antibody-drug conjugate (ADC) for cancer therapy

Goldenberg, David M.; Sharkey, Robert M.

doi:10.1080/14712598.2020.1757067

Cited by 73 publications

(68 citation statements)

References 115 publications

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“…SN-38 is an active metabolite of irinotecan, the chemotherapeutic agent often used for clinical management of colorectal carcinomas [ 159 ]. The development of this conjugate and the results of preclinical and clinical studies in various cancer types have been reviewed recently [ 160 , 161 ]. These studies demonstrated a significant clinical response, good pharmacokinetic profile, no immunogenicity, and manageable toxicity of sacituzumab govitecan in heavily pretreated metastatic cancers, especially in triple-negative breast cancer (TNBC) [ 162 , 163 , 164 , 165 , 166 , 167 , 168 , 169 , 170 , 171 ].…”

Section: Trop2 In Cancermentioning

confidence: 99%

“…Unfortunately, clinical studies have not provided conclusive evidence that Trop2 levels predicted responsiveness to sacituzumab govitecan, possibly because of the high frequency of strong positive specimens [ 161 ]. Further clinical studies are therefore needed to select patients for this type of therapy, including those with less advanced disease, to investigate effective therapeutic combinations and to find suitable predictive markers.…”

Section: Trop2 In Cancermentioning

confidence: 99%

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Trop2: Jack of All Trades, Master of None

Lenárt

Šmarda

et al. 2020

Cancers

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Trophoblast cell surface antigen 2 (Trop2) is a widely expressed glycoprotein and an epithelial cell adhesion molecule (EpCAM) family member. Although initially identified as a transmembrane protein, other subcellular localizations and processed forms were described. Its congenital mutations cause a gelatinous drop-like corneal dystrophy, a disease characterized by loss of barrier function in corneal epithelial cells. Trop2 is considered a stem cell marker and its expression associates with regenerative capacity in various tissues. Trop2 overexpression was described in tumors of different origins; however, functional studies revealed both oncogenic and tumor suppressor roles. Nevertheless, therapeutic potential of Trop2 was recognized and clinical studies with drug–antibody conjugates have been initiated in various cancer types. One of these agents, sacituzumab govitecan, has been recently granted an accelerated approval for therapy of metastatic triple-negative breast cancer. In this article, we review the current knowledge about the yet controversial function of Trop2 in homeostasis and pathology.

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Section: Trop2 In Cancermentioning

confidence: 99%

Section: Trop2 In Cancermentioning

confidence: 99%

Trop2: Jack of All Trades, Master of None

Lenárt

Šmarda

et al. 2020

Cancers

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“…[1][2][3][4][5][6] Antibodydrug conjugates (ADCs), comprising monoclonal antibodies conjugated to cytotoxic agents (payloads) via a linker, have emerged as novel therapeutic options. [7][8][9][10] ADCs have been approved for the treatment of metastatic urothelial cancer (mUC), metastatic breast cancer, and hematological malignancies, [11][12][13][14][15][16][17][18][19][20][21] and several are currently in clinical development. 7 They represent significant progress for the treatment of advanced cancers, as ADCs offer tumor specificity and potency not achievable with traditional therapeutic options while limiting the toxicity associated with an unconjugated payload.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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“…Antibody drug conjugates (ADCs) provide targeted delivery of potent cytotoxic agents to tumor cells by binding to antigens that are specifically expressed and/or upregulated on tumor cells. The eight ADCs that are currently approved and commercialized as therapeutic agents for treatment of multiple solid and hematological malignancies have heralded in a new wave of clinical development of ADCs, 1 with an additional upcoming approval in relapsed/refractory myeloma. There are currently > 50 ADCs in clinical development for various hematological malignancies and solid tumors, and > 200 clinical trials involving ADCs 2 .…”

mentioning

confidence: 99%

Mechanistic Modeling of Intra‐Tumor Spatial Distribution of Antibody‐Drug Conjugates: Insights into Dosing Strategies in Oncology

Weddell

Chiney

Bhatnagar

et al. 2020

Clinical Translational Sci

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Antibody drug conjugates (ADCs) provide targeted delivery of cytotoxic agents directly inside tumor cells. However, many ADCs targeting solid tumors have exhibited limited clinical efficacy, in part, due to insufficient penetration within tumors. To better understand the relationship between ADC tumor penetration and efficacy, previously applied Krogh cylinder models that explore tumor growth dynamics following ADC administration in preclinical species were expanded to a clinical framework by integrating clinical pharmacokinetics, tumor penetration, and tumor growth inhibition. The objective of this framework is to link ADC tumor penetration and distribution to clinical efficacy. The model was validated by comparing virtual patient population simulations to observed overall response rates from trastuzumab‐DM1 treated patients with metastatic breast cancer. To capture clinical outcomes, we expanded upon previous Krogh cylinder models to include the additional mechanism of heterogeneous tumor growth inhibition spatially across the tumor. This expansion mechanistically captures clinical response rates by describing heterogeneous ADC binding and tumor cell killing; high binding and tumor cell death close to capillaries vs. low binding, and high tumor cell proliferation far from capillaries. Sensitivity analyses suggest that clinical efficacy could be optimized through dose fractionation, and that clinical efficacy is primarily dependent on the ADC‐target affinity, payload potency, and tumor growth rate. This work offers a mechanistic basis to predict and optimize ADC clinical efficacy for solid tumors, allowing dosing strategy optimization to improve patient outcomes.

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Sacituzumab govitecan, a novel, third-generation, antibody-drug conjugate (ADC) for cancer therapy

Cited by 73 publications

References 115 publications

Trop2: Jack of All Trades, Master of None

Trop2: Jack of All Trades, Master of None

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

Mechanistic Modeling of Intra‐Tumor Spatial Distribution of Antibody‐Drug Conjugates: Insights into Dosing Strategies in Oncology

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