TRODELVY Powder for solution for infusion Ref.[10365] Active ingredients: Sacituzumab govitecan

Exposure-response relationships and the time course of pharmacodynamics response are unknown for sacituzumab govitecan-hziy.

The serum pharmacokinetics of sacituzumab govitecan-hziy and SN-38 were evaluated in a study in a population of mTNBC patients who received sacituzumab govitecan-hziy as a single agent at a dose of 10 mg/kg. The pharmacokinetic parameters of sacituzumab govitecan-hziy and free SN-38 are presented in Table 4.

Table 4. Summary of Mean PK Parameters (±Standard Deviation) of Sacituzumab Govitecan-hziy and Free SN-38:

C_max: maximum plasma concentration
AUC_0-168: area under plasma concentration curve through 168 hours

Distribution

The mean volume of distribution for sacituzumab govitecan-hziy was 0.045 L/kg.

Elimination

The mean half-life of sacituzumab govitecan-hziy and free SN-38 was 16 and 18 hours, respectively. The clearance of the sacituzumab govitecan-hziy was 0.002 L/h/kg.

Metabolism

No metabolism studies with sacituzumab govitecan-hziy have been conducted. SN-38 (the small molecule moiety of sacituzumab govitecan-hziy) is metabolized via UGT1A1. The glucuronide metabolite of SN-38 (SN-38G) was detectable in the serum of patients.

Specific Populations

Pharmacokinetic analyses in a limited number of patients with mTNBC (n=57) did not identify an effect of age or race on the pharmacokinetics of sacituzumab govitecan-hziy. Renal elimination is known to contribute minimally to the excretion of SN-38, the small molecule moiety of sacituzumab govitecan-hziy. There are no data on the pharmacokinetics of sacituzumab govitecan-hziy in patients with renal impairment or end-stage renal disease (CLcr ≤30 mL/min).

The exposure of sacituzumab govitecan-hziy is similar in patients with mild hepatic impairment (bilirubin less than or equal to ULN and AST greater than ULN, or bilirubin greater than 1.0 to less than 1.5 ULN and AST of any level; n=12) to patients with normal hepatic function (bilirubin or AST less than ULN; n=45).

Sacituzumab govitecan-hziy exposure is unknown in patients with moderate or severe hepatic impairment. SN-38 exposure may be elevated in such patients due to decreased hepatic UGT1A1 activity.

Drug Interaction Studies

No drug-drug interaction studies were conducted with sacituzumab govitecan-hziy or its components Inhibitors or inducers of UGT1A1 are expected to increase or decrease SN-38 exposure, respectively [see Drug Interactions (7)].

SN-38 is metabolized via UGT1A1 [see Clinical Pharmacology (12.3)]. Genetic variants of the UGT1A1 gene such as the UGT1A1*28 allele lead to reduced UGT1A1 enzyme activity. Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia from TRODELVY [see Warnings and Precautions (5.5)]. Approximately 20% of the Black or African American population, 10% of the White population, and 2% of the East Asian population are homozygous for the UGT1A1*28 allele. Decreased function alleles other than UGT1A1*28 may be present in certain populations.

Carcinogenicity studies have not been conducted with sacituzumab govitecan-hziy.

SN-38 was clastogenic in an in vitro mammalian cell micronucleus test in Chinese hamster ovary cells and was not mutagenic in an in vitro bacterial reverse mutation (Ames) assay.

Fertility studies with sacituzumab govitecan-hziy have not been conducted. In a repeat-dose toxicity study in cynomolgus monkeys, intravenous administration of sacituzumab govitecan-hziy on Day 1 and Day 4 resulted in endometrial atrophy, uterine hemorrhage, increased follicular atresia of the ovary, and atrophy of vaginal epithelial cells at doses ≥60 mg/kg (≥6 times the human recommended dose of 10 mg/kg based on body weight).

The efficacy of TRODELVY was evaluated in study IMMU-132-01 (NCT01631552), a multicenter, single-arm, trial that enrolled 108 patients with metastatic triple-negative breast cancer (mTNBC) who had received at least two prior treatments for metastatic disease. Patients with bulky disease, defined as a mass >7 cm, were not eligible. Patients with treated brain metastases not receiving high dose steroids (>20 mg prednisone or equivalent) for at least four weeks were eligible. Patients with known Gilbert’s disease were excluded.

Patients received TRODELVY 10 mg/kg intravenously on Days 1 and 8 of a 21-day treatment cycle. Patients were treated with TRODELVY until disease progression or intolerance to the therapy. Tumor imaging was obtained every 8 weeks, with confirmatory CT/MRI scans obtained 4-6 weeks after an initial partial or complete response, until progression requiring treatment discontinuation. Major efficacy outcome measures were investigator assessed overall response rate (ORR) using RECIST 1.1 and duration of response.

The median age was 55 years (range: 31-80 years); 87% of patients were younger than 65 years. The majority of patients were female (99%), and White (76%). At study entry, all patients had an ECOG performance status of 0 (29%) or 1 (71%). Seventy-six percent had visceral disease, 42% had hepatic metastases, 56% had lung/pleura metastases, and 2% had brain metastases. Twelve patients (11%) had Stage IV disease at the time of initial diagnosis.

The median number of prior systemic therapies received in the metastatic setting was 3 (range: 2-10). Prior chemotherapies in the metastatic setting included carboplatin or cisplatin (69%), gemcitabine (55%), paclitaxel or docetaxel (53%), capecitabine (51%), eribulin (45%), doxorubicin (24%), vinorelbine (16%), cyclophosphamide (19%), and ixabepilone (8%).

Overall, 98% of patients had received prior taxanes and 86% had received prior anthracyclines either in the (neo)adjuvant or metastatic setting.

Table 5 summarizes the efficacy results.

Table 5. Efficacy results for patients with mTNBC in IMMU-132-01:

ⁱ investigator assessment
CI: confidence interval
⁺ denotes ongoing