CYP3A nor induce CYP1A2, CYP2B6, or CYP3A [15]. Dxd has low potential to inhibit OAT1/3, OCT1/2, OATP1B1/3, MATE1/2-K, P-gp, BCRP, and BSEP transporters [15].

#### **4.3 SG**

No formal drug interaction studies were conducted with SG or SN-38 [16]. Given metabolism and clearance mechanism of SN-38 via UGT1A1, UGT1A1 inhibitors may increase the concentration and toxicity of SN-38 and thus coadministration should be avoided. Additionally, UGT1A1 inducers may decrease exposure to SN-38 and its efficacy [16].

There are challenges with drug interaction assessment with ADCs. There is no specific guidance from regulatory bodies on how to formally evaluate drug interactions with cytotoxic payloads. There is an unmet need for understanding how cytotoxic payloads will be affected by oxidative enzymes and drug transporters. It is speculated that given the low systemic exposure, cytotoxic payload molecules are unlikely to cause clinically meaningful interactions but can be significantly affected by enzymes and transporters. Unique considerations may be needed when designing PK studies to evaluate interactions with cytotoxic payloads [45].

### **5. Pharmacogenomics**

The cytotoxic payload, SN-38 in SG is metabolized via UGT1A1 to an inactive metabolite. The genetic variant UGT1A1\*28 has reduced enzyme activity. Patients who are homozygous (UGT1A1\*28/\*28; diminished enzyme activity) and heterozygous (UGT1A1\*28/\*1; reduced enzyme activity) are at increased risk for neutropenia, febrile neutropenia, anemia, and other toxicities due to increased exposure to SN-38 compared to wild type (UGT1A1\*1/\*1; normal enzyme activity) [16, 46]. There are no known pharmacogenomics implications for T-DM1 and T-Dxd [14, 15].

The frequency of having homozygous UGT1A1\*28 allele varies with about 20% of the Black population, 10% of the White population, and 2% of the East Asian population are homozygous for the UGT1A1\*28 allele [47]. Approximately, 40% of Black, 50% of White, and 25% of East Asian population are heterozygous for the UGT1A1\*28 allele [47].

Patients presenting with acute-onset, severe neutropenia and anemia may indicate reduced UGT1A1 enzyme activity. The median time to neutropenia and febrile neutropenia was 9 days in patients who are homozygous for UGT1A1\*28 allele, 15 days in patients who are heterozygous for the allele, and 20 days who are wild type for UGT1A1\* [16]. The median time to anemia in patients homozygous for UGT1A1\*28, heterozygous for UGT1A1\*28, and homozygous for wild type UGT1A1\* was 21 days, 25 days, and 28 days, respectively [16].

In a safety analysis from phase III, randomized clinical trial of SG in metastatic TNBC, the impact of UGT1A1 polymorphism was evaluated. In patients treated with SG, UGT1A1 genotype was known for 250 patients. Of 250 patients, 113 (44%), 96 (37%), and 34 (13%) were homozygous for the wild type UGT1A1 (\*1/\*1), heterozygous (\*1/\*28), and homozygous (\*28/\*28) [48]. Patients with homozygous \*28 genotype had comparable grade 3/4 neutropenia (59%) to those with heterozygous \*28 (47%) or wild type (53%), but the rate of febrile neutropenia was higher (18% vs. 5% and 3%, respectively). Grades 3/4 anemia (15% vs. 6% and 4%, respectively) and diarrhea (15% vs. 9% and 10%, respectively) occurred more frequently in patients with homozygous

UGT1A1\*28 genotype compared to those with heterozygous and wild type genotypes. Treatment discontinuation due to adverse events was also more common in patients with homozygous UGT1A1\*28 genotype compared to heterozygous \*28 and wild type genotypes (6%, 1%, and 2%, respectively). Other adverse events including nausea, vomiting, fatigue and alopecia were not impacted by UGT1A1 genotype [48].

Increased risk for severe adverse reactions including neutropenia and febrile neutropenia with irinotecan in patients with reduced UGT1A1 activity is attributed to its active metabolite, SN-38, which is the cytotoxic payload of SG [49, 50]. While the FDA recommends reducing the starting dose of irinotecan in patients with colorectal cancer and known UGT1A1\*28/\*28 status [50], there are currently no guidelines for SG dosing recommendations for patients who have known UGT1A1\*28/\*28 genotype. The FDA only recommends SG dose modification or discontinuation based on tolerance [16].
