Prescription Drug Information: TRODELVY (Page 4 of 5)

12.5 Pharmacogenomics

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, febrile neutropenia, and anemia 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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).

14 CLINICAL STUDIES

14.1 Locally Advanced or Metastatic Triple-Negative Breast Cancer

ASCENT

Efficacy was evaluated in a multicenter, open-label, randomized study (ASCENT; NCT02574455) conducted in 529 patients with unresectable locally advanced or metastatic triple-negative breast cancer (mTNBC) who had relapsed after at least two prior chemotherapies for breast cancer (one of which could be in the neoadjuvant or adjuvant setting provided progression occurred within a 12 month period). All patients received previous taxane treatment in either the adjuvant, neoadjuvant, or advanced stage unless there was a contraindication or intolerance to taxanes during or at the end of the first taxane cycle. Magnetic resonance imaging (MRI) to determine brain metastases was required prior to enrollment for patients with known or suspected brain metastases. Patients with brain metastases were allowed to enroll up to a pre-defined maximum of 15% of patients in the ASCENT trial. Patients with known Gilbert’s disease or bone-only disease were excluded.

Patients were randomized (1:1) to receive TRODELVY 10 mg/kg as an intravenous infusion on Days 1 and 8 of a 21-day (n=267) or physician’s choice of single agent chemotherapy (n=262). Single agent chemotherapy was determined by the investigator before randomization from one of the following choices: eribulin (n=139), capecitabine (n=33), gemcitabine (n=38), or vinorelbine (n=52).

Patients were treated until disease progression or unacceptable toxicity. The major efficacy outcome was progression-free survival (PFS) in patients without brain metastases at baseline (i.e., BMNeg) as measured by a blinded, independent, centralized review assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 criteria. Additional efficacy measures included PFS for the full population (all patients with and without brain metastases) and overall survival (OS).

The median age of patients in the full population (n = 529) was 54 years (range: 27–82 years); 99.6% were female; 79% were White, 12% were Black/African American; and 81% of patients were < 65 years of age. All patients had an ECOG performance status of 0 (43%) or 1 (57%). Forty-two percent of patients had hepatic metastases, 9% were BRCA1/BRCA2 mutational status positive, and 70% were TNBC at diagnosis. Twelve percent had baseline brain metastases previously treated and stable (n=61; 32 on TRODELVY arm and 29 on single agent chemotherapy arm). Overall, 29% of patients had received prior PD-1/PD-L1 therapy. Thirteen percent of patients in the TRODELVY group in the full population received only 1 prior line of systemic therapy in the metastatic setting.

The efficacy results are summarized in Table 9 and are shown in Figure 1 and Figure 2. Efficacy results for the subgroup of patients who had received only 1 prior line of systemic therapy in the metastatic setting (in addition to having disease recurrence or progression within 12 months of neoadjuvant/adjvuant systemic therapy) were consistent with those who had received at least two prior lines in the metastatic setting.

Table 9: Efficacy Results from ASCENT
All Randomized Patients
TRODELVYn=267Single Agent Chemotherapyn=262
CI = Confidence Interval
*
PFS is defined as the time from the date of randomization to the date of the first radiological disease progression or death due to any cause, whichever comes first.
Stratified log-rank test adjusted for stratification factors: number of prior chemotherapies, presence of known brain metastases at study entry, and region.
Progression-Free Survival * per BICR
Disease Progression or Death (%)190 (71%)171 (65%)
Median PFS in months (95% CI)4.8(4.1, 5.8)1.7(1.5, 2.5)
Hazard ratio (95% CI)0.43 (0.35, 0.54)
p-value<0.0001
Overall Survival
Deaths (%)179 (67%)206 (79%)
Median OS in months (95% CI)11.8(10.5, 13.8)6.9(5.9, 7.6)
Hazard ratio (95% CI)0.51 (0.41, 0.62)
p-value<0.0001

Figure 1: Kaplan-Meier Plot of PFS by BICR (All Randomized Patients) in ASCENT

Figure 1
(click image for full-size original)

Figure 2: Kaplan-Meier Plot of OS (All Randomized Patients) in ASCENT

Figure 2
(click image for full-size original)

An exploratory analysis of PFS in patients with previously treated, stable brain metastases showed a stratified HR of 0.65 (95% CI: 0.35, 1.22). The median PFS in the TRODELVY arm was 2.8 months (95% CI: 1.5, 3.9) and the median PFS with single agent chemotherapy was 1.6 months (95% CI: 1.3, 2.9). Exploratory OS analysis in the same population showed a stratified HR of 0.87 (95% CI: 0.47, 1.63). The median OS in the TRODELVY arm was 6.8 months (95% CI: 4.7, 14.1) and the median OS with single agent chemotherapy was 7.4 months (95% CI: 4.7, 11.1).

IMMU-132-01

The efficacy of TRODELVY was evaluated in a multicenter, single-arm, trial (NCT01631552) 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 10 summarizes the efficacy results.

Table 10: Efficacy results for patients with mTNBC in IMMU-132-01
TRODELVY(N=108)
CI: confidence interval
+: denotes ongoing
*
investigator assessment
Overall Response Rate *
ORR (95% CI)33.3% (24.6, 43.1)
Complete response2.8%
Partial response30.6%
Response duration *
Number of responders36
Median, Months (95% CI)7.7 (4.9, 10.8)
Range, Months1.9+, 30.4+
% with duration ≥6 months55.6%
% with duration ≥12 months16.7%

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