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

Abstract

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.

Keywords: Antibody drug conjugates; Breast cancer; Toxicity management.

Fig. 1

Main AEs described with ADCs for BC treatment. Drugs needing prophylaxis use or medical/laboratory screening are indicated. Created with BioRender.com.

Fig. 2

Hematological AEs monitoring and management. Hematological toxicities may have life-threatening consequences, therefore complete blood count (CBC) assessment is always recommended before ADC administration. Blood counts should be also monitored periodically during the treatment, in addition to evaluating the possible interactions with other medication. As described in the present figure, in case of adverse events, dose adjustment or discontinuation may be needed.

Fig. 3

Monitoring and management of T-DM1 (a) and T-DXd (b) related cardiovascular toxicity. In metastatic HER2-positive disease, TTE is recommended every 3 months during the first year and, in absence of cardiovascular toxicity, every 6 months. In early-stage BC, it is recommended to perform TTE every 3 months during anti-HER2 treatment and within 12 months after completion. Created with BioRender.com.

Fig. 4

Nausea and vomiting prophylaxis regimens. For moderate-emetogenic agents, a 2-drugs prophylactic regimen can be administered on day 1 of each cycle. It should include a 5-HT3 receptor antagonist (RA) (e.g., ondansetron, palonosetron, granisetron) and dexamethasone (DMX). For high-risk patients (e.g., young women with little use of alcohol or who previously experienced NV), or in case of refractory emesis, a NK1 RA can be added (e.g., aprepitant, fosaprepitant, netupitant) in a 3-drug regimen. For delayed-onset emesis, single agent 5-HT3 RA or DMX can be offered on day 2 and 3 after the standard prophylactic regimen administered on day 1; alternatively, aprepitant (with or without DMX) can be employed if the NK-1 RA had been administered on day 1. Importantly, given their long duration of action, palonosetron and NK1 RAs other then aprepitant must not be continued at day 2–3 as well as granisetron subcutaneous or transdermal. For low emetogenic agents NCCN guidelines recommend single agent therapy with DMX 8–12 mg or single dose metoclopramide 10–20 mg or prochlorperzane 10 mg or single dose 5-HT3 RA.