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      Toxicity profile of antibody-drug conjugates in breast cancer: practical considerations

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          Summary

          Antibody–drug conjugates (ADCs) represent a novel and evolving class of antineoplastic agents, constituted by monoclonal antibody linked to biologically active drugs, delivering cytotoxic compounds at the tumor site, reducing the likelihood of systemic exposure and toxicity. They are generally well tolerated, nevertheless some predictable adverse reactions need careful monitoring and timely approach. These include neutropenia, nausea and vomiting, alopecia, diarrhea, left ventricular dysfunction, ILD/pneumonitis. The mechanisms leading to drug-associated toxicities are summarized, and prophylaxis protocols and appropriate management strategies are proposed, based on current literature. This review aims to collect the most updated evidence on toxicities potentially occurring during breast cancer treatment with approved or under clinical investigation (advanced stage) ADCs. A focus is dedicated to monitoring protocols and clinical management, aimed at preventing and/or promptly address relevant problems, in order to avoid premature discontinuation or improper dose reduction.

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          Most cited references85

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          Trastuzumab Emtansine for Residual Invasive HER2-Positive Breast Cancer

          Patients who have residual invasive breast cancer after receiving neoadjuvant chemotherapy plus human epidermal growth factor receptor 2 (HER2)-targeted therapy have a worse prognosis than those who have no residual cancer. Trastuzumab emtansine (T-DM1), an antibody-drug conjugate of trastuzumab and the cytotoxic agent emtansine (DM1), a maytansine derivative and microtubule inhibitor, provides benefit in patients with metastatic breast cancer that was previously treated with chemotherapy plus HER2-targeted therapy.
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            Trastuzumab Deruxtecan in Previously Treated HER2-Positive Breast Cancer

            Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate composed of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. In a phase 1 dose-finding study, a majority of the patients with advanced HER2-positive breast cancer had a response to trastuzumab deruxtecan (median response duration, 20.7 months). The efficacy of trastuzumab deruxtecan in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab emtansine requires confirmation.
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              Trastuzumab emtansine for HER2-positive advanced breast cancer.

              Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate incorporating the human epidermal growth factor receptor 2 (HER2)-targeted antitumor properties of trastuzumab with the cytotoxic activity of the microtubule-inhibitory agent DM1. The antibody and the cytotoxic agent are conjugated by means of a stable linker. We randomly assigned patients with HER2-positive advanced breast cancer, who had previously been treated with trastuzumab and a taxane, to T-DM1 or lapatinib plus capecitabine. The primary end points were progression-free survival (as assessed by independent review), overall survival, and safety. Secondary end points included progression-free survival (investigator-assessed), the objective response rate, and the time to symptom progression. Two interim analyses of overall survival were conducted. Among 991 randomly assigned patients, median progression-free survival as assessed by independent review was 9.6 months with T-DM1 versus 6.4 months with lapatinib plus capecitabine (hazard ratio for progression or death from any cause, 0.65; 95% confidence interval [CI], 0.55 to 0.77; P<0.001), and median overall survival at the second interim analysis crossed the stopping boundary for efficacy (30.9 months vs. 25.1 months; hazard ratio for death from any cause, 0.68; 95% CI, 0.55 to 0.85; P<0.001). The objective response rate was higher with T-DM1 (43.6%, vs. 30.8% with lapatinib plus capecitabine; P<0.001); results for all additional secondary end points favored T-DM1. Rates of grade 3 or 4 adverse events were higher with lapatinib plus capecitabine than with T-DM1 (57% vs. 41%). The incidences of thrombocytopenia and increased serum aminotransferase levels were higher with T-DM1, whereas the incidences of diarrhea, nausea, vomiting, and palmar-plantar erythrodysesthesia were higher with lapatinib plus capecitabine. T-DM1 significantly prolonged progression-free and overall survival with less toxicity than lapatinib plus capecitabine in patients with HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. (Funded by F. Hoffmann-La Roche/Genentech; EMILIA ClinicalTrials.gov number, NCT00829166.).
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                Author and article information

                Contributors
                Journal
                eClinicalMedicine
                EClinicalMedicine
                eClinicalMedicine
                Elsevier
                2589-5370
                27 July 2023
                August 2023
                27 July 2023
                : 62
                : 102113
                Affiliations
                [a ]Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Via Sergio Pansini 5, Naples 80131, Italy
                [b ]Scuola Superiore Meridionale (SSM), Clinical and Translational Oncology, Via Mezzocannone 4, Naples 80138, Italy
                [c ]Molecular Predictors and New Targets in Oncology Unit 981, Gustave Roussy, 114 Rue Édouard-Vaillant, Villejuif 94805, France
                [d ]Oncology Unit, PO di San Felice a Cancello, Via Roma 349, San Felice a Cancello, Caserta 81021, Italy
                [e ]Department of Oncology, HFR Fribourg-Cantonal Hospital, Chemin des Pensionnats 2-6, Fribourg 1708, Switzerland
                [f ]Division of Breast Medical Oncology, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Via Mariano Semmola 52, Naples 80131, Italy
                [g ]Department of Medicine, University of Udine, Via Palladio 8, Udine 33100, Italy
                [h ]Department of Medical Oncology, CRO Aviano, National Cancer Institute, IRCCS, Via Franco Gallini 2, Aviano, Pordenone 33081, Italy
                [i ]Department of Medical Oncology, UO Oncologia Medica 2, IRCCS Ospedale Policlinico San Martino, Largo R. Benzi 10, Genova 16132, Italy
                [j ]Candiolo Cancer Institute, FPO-IRCCS, Strada Provinciale 142 -KM 3.95, Candiolo, Torino 10060, Italy
                Author notes
                []Corresponding author. Molecular Predictors and New Targets in Oncology Unit 981, Gustave Roussy, 114 rue Édouard-Vaillant, Villejuif 94805, France. Martina.PAGLIUCA@ 123456gustaveroussy.fr
                [∗∗ ]Corresponding author. Department of Clinical Medicine and Surgery, University of Naples “Federico II”, Via Sergio Pansini 5, Naples 80131, Italy. fabiana.napolitano@ 123456unina.it
                [∗∗∗ ]Corresponding author. Division of Breast Medical Oncology, Istituto Nazionale Tumori IRCCS “Fondazione G. Pascale”, Via Mariano Semmola 52, Naples 80131, Italy. m.delaurentiis@ 123456istitutotumori.na.it
                [k]

                Contributed equally to the manuscript.

                [l]

                Contributed equally to the manuscript.

                [m]

                Co-first authors.

                [n]

                Co-last authors.

                Article
                S2589-5370(23)00290-0 102113
                10.1016/j.eclinm.2023.102113
                10404866
                37554126
                6287169c-0c93-4c6d-b723-3fb067091128
                © 2023 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 22 May 2023
                : 3 July 2023
                : 5 July 2023
                Categories
                Review

                antibody drug conjugates,breast cancer,toxicity management

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