**7. Adverse events and monitoring**

#### **7.1 T-DM1**

The most common adverse events associated with T-DM1 were musculoskeletal pain (37.9%), nausea (40.6%), thrombocytopenia (45.7%), constipation (26.9%), fatigue (38.8%), and transaminitis (36.8%). T-DM1 has a low emetic risk [2]. T-DM1 is not associated with alopecia. Due to hepatotoxicity, it is recommended to monitor bilirubin and transaminases before each dose of T-DM1.

Decreased left ventricular ejection fraction (LVEF) has been observed with anti-HER2 therapies including T-DM1 (2–3%). Patients with history of significant cardiac disease and those with baseline LVEF <50% were excluded from clinical trials. It is recommended to monitor left ventricular ejection fraction (LVEF) before initiating T-DM1 and throughout treatment [14]. In clinical practice, LVEF is typically monitored prior to initiating treatment with T-DM1 and every 3 months thereafter.

#### **7.2 T-Dxd**

The most common hematologic adverse events associated with T-Dxd were decrease in hemoglobin (66%), white blood cells (71%), neutrophil (65%), platelets (47%), and lymphocyte (55%). The most common non-hematologic adverse events were fatigue, increase in aminotransferases, constipation, vomiting, decreased appetite, musculoskeletal pain, diarrhea, and hypokalemia [15]. T-Dxd is considered highly emetogenic [2]. T-Dxd is associated with alopecia (21 to 46%). An increased incidence

of interstitial lung disease (ILD)/pneumonitis including fatal events were observed in clinical trials (all grade, 15.4%; grades 1/2,11.9%; grades 3/4,1.3%; grade 5 or death, 2.2%). Median time to onset is approximately 5.4 months (range, <0.1–46.8 mo). Risk factors include moderate to severe kidney impairment, having pulmonary comorbidities at baseline (i.e., asthma, prior ILD, radiation pneumonitis), time since initial cancer diagnosis >4 years, age <65 years, baseline oxygen saturation < 95%, and T-Dxd dose >6.4 mg/kg. No consensus guidelines exist on type and frequency of monitoring besides symptoms assessment. High resolution chest computed tomography (CT) was obtained every 6 weeks in clinical trials investigating T-Dxd. Frequent imaging mimicking clinical trials may not be feasible in clinical practice for reasons such as cost and insurance coverage. As a result, frequent monitoring for ILD symptoms in patients receiving T-Dxd is imperative. Similarly to T-DM1, LVEF reduction was reported with T-Dxd (3–8%; mostly asymptomatic) it is recommended to monitor LVEF before starting and periodically thereafter [15]. In clinical practice, LVEF is typically monitored prior to initiating treatment with T-Dxd and every 3 months thereafter.

#### **7.3 SG**

The most common adverse events associated with SG were febrile neutropenia (6%), vomiting (5%), diarrhea (4%), dyspnea (3%), nausea (3%), and anemia (2%). It is recommended to monitor patients for severe neutropenia with known reduced activity of UGT1A1 (see pharmacogenomics for details) [16].

## **8. ADCs in development**

Datopotamab deruxtecan (DS-1062) or Dato-Dxd is a Trop2 ADC with a topoisomerase I inhibitor payload (Dxd). Dato-Dxd is comprised of a humanized IgG1 mAb conjugated to the cytotoxic payload via a cleavable, tetrapeptide based linker, and it has an average of 4 DAR with demonstrated bystander effect [63]. Dato-Dxd is being investigated in ongoing clinical trials in solid tumors including breast cancer [64].

Dato-Dxd is being investigated in heavily pretreated patients with metastatic TNBC in the TROPIONPanTumor01 trial (NCT03401385) and has demonstrated encouraging results with an objective response rate of 34% in all patients and 52% in patients who are treatment-naïve to topoisomerase I inhibitor-based therapies [64]. Most common adverse events reported with Dato-Dxd were stomatitis (all grade, 73%; grade 3, 11%), nausea (all grade, 66%; grade 3, 2%), and vomiting (all grade, 39%; grade 3, 5%). The incidence of alopecia was 36% (grade 2, 14%) [64].

Dato-Dxd is also being investigated in the TROPION-Breast01 (NCT05104866), an ongoing randomized, phase III trial that enrolled 700 patients with metastatic, HR+ HER2 negative breast cancer. Patients are randomized 1:1 to Dato-Dxd or chemotherapy (eribulin, capecitabine, vinorelbine, or gemcitabine). Included patients had to have progressed on endocrine therapy and 1–2 prior lines of chemotherapy [65]. Results are not yet reported.

#### **9. Conclusion**

ADCs combine precision targeting with traditional cytotoxic treatment allowing for the delivery of highly potent chemotherapeutic agents to malignant cells. Recent *Antibody Drug Conjugates DOI: http://dx.doi.org/10.5772/intechopen.110804*

regulatory approvals of next generation ADCs have changed how breast cancer is classified and treated. There are three approved ADCs for the treatment of breast cancer to this dare, and more ADCs are currently in development.
