Sacituzumab Govitecan Elicits Consistent Safety in Patients With HR+/HER2– Breast Cancer, Regardless of UGT1A1 Status

Sacituzumab govitecan-hziy (Trodelvy) displayed a manageable safety profile consistent with previous reports in patients with hormone receptor–positive, HER2-negative metastatic breast cancer, irrespective of UGT1A1 status, according to a safety analysis of the phase 3 TROPiCS-02 trial (NCT03901339) presented at the 2023 ESMO Breast Cancer Annual Congress.¹

Among the 272 patients in the sacituzumab govitecan arm, 268 were evaluable for UGT1A1 status. Thirty-eight percent of patients (n = 103) were UGT1A1 *1/*1 wild-type, 44% (n = 119) were UGT1A1 *1/*28 heterozygous, and 9% (n = 25) were UGT1A1 *28/*28 homozygous.

All patients treated with sacituzumab govitecan experienced at least 1 any-grade treatment-emergent adverse effect (TEAE). The rates of grade 3 or higher TEAEs were 67%, 75%, and 92% in patients with wild-type, heterozygous, and homozygous UGT1A1 genotypes, respectively.

Twenty-five percent of with wild-type UGT1A1 experienced TEAEs that led to dose reduction, compared with 41% of patients with heterozygous UGT1A1 and 40% of patients with homozygous UGT1A1. The rates of TEAEs leading to treatment interruption across the 3 subgroups were 68%, 64%, and 76%, respectively. Five percent of patients with wild-type UGT1A1 discontinued treatment due to TEAEs, compared with 6% of patients with heterozygous UGT1A1 and 12% of patients with homozygous UGT1A1.

Among all patients treated with sacituzumab govitecan, grade 3 and higher TEAEs of special interest included neutropenia (51%), diarrhea (10%), anemia (7%), and febrile neutropenia (6%).

Notably, patients with homozygous UGT1A1 experienced increased rates of grade 3 or higher neutropenia (64%) compared with wild-type (45%) and heterozygous (57%) genotypes. Twenty-four percent of patients with homozygous UGT1A1 had grade 3 or higher diarrhea, compared with 6% for patients with wild-type genotype and 13% for those with heterozygous genotype. Forty-eight percent of patients with homozygous UGT1A1 had any-grade anemia vs patients with wild-type (33%) or heterozygous (36%) genotypes. Rates of febrile neutropenia were similar across subgroups.

“Patients who were homozygous for UGT1A1 *28/*28 experienced numerically higher rates of grade 3 [or higher] TEAEs, TEAEs leading to discontinuation, any-grade anemia, and grade 3 [or higher] diarrhea and neutropenia, although sample sizes were small,” lead study author, Frederik Marmé, MD, PhD, of Universitätsmedizin Mannheim, in Heidelberg, Germany, and colleagues, noted in the poster presentation.

“Because patients treated with sacituzumab govitecan are closely monitored for AEs according to the prescribing information and per standard practice regardless of UGT1A1 genotype, UGT1A1 testing is not needed for sacituzumab govitecan use in [patients with] pretreated hormone receptor–positive/HER2-negative metastatic breast cancer.”

Prior data from the TROPiCS-02 trial supported the February 2023 FDA approval of sacituzumab govitecan for the treatment of adult patients with unresectable locally advanced or metastatic hormone receptor–positive, HER2-negative breast cancer who have received endocrine-based therapy and at least 2 additional systemic therapies in the metastatic setting.²

Findings showed that sacituzumab govitecan elicited a median progression-free survival (PFS) of 5.5 months (95% CI, 4.2-7.0) compared with 4.0 months (95% CI, 3.1-4.4) with chemotherapy (HR, 0.661; 95% CI, 0.529-0.826; P = .0003). Additionally, patients treated with the antibody-drug conjugate achieved a median overall survival (OS) of 14.4 months (95% CI, 13.0-15.7) vs 11.2 months (95% CI, 10.1-12.7) for those given chemotherapy (HR, 0.789; 95% CI, 0.646-0.964; P = .02).³

Polymorphisms associated with UGT1A1 have been associated with a greater incidence of AEs, including neutropenia, febrile neutropenia, anemia, and diarrhea, following treatment with some systemic anticancer agents due to a reduced rate of SN-38 glucuronidation. Marmé and colleagues analyzed safety outcomes for patients in the sacituzumab govitecan arm of the TROPiCS-02 trial based on UGT1A1 status.

The randomized, open-label phase 3 trial enrolled patients with metastatic or locally recurrent inoperable hormone receptor–positive, HER2-negative breast cancer that progressed following at least 1 endocrine therapy, taxane, and CDK4/6 inhibitor in any setting, and at least 2, but no more than 4, lines of chemotherapy in the metastatic setting. Additionally, patients were required to have measurable disease per RECIST v1.1 criteria.

Eligible patients were randomly assigned in a 1:1 fashion to receive either intravenous sacituzumab govitecan at 10 mg/kg on days 1 and 8 every 21 days (n = 272), or physician’s choice of treatment consisting of capecitabine, vinorelbine, gemcitabine, or eribulin (n = 271). Treatment continued until progression or unacceptable toxicity.

The primary end point of the study was PFS. Secondary end points included OS, overall response rate, duration of response, clinical benefit rate, patient-reported outcomes, and safety. UGT1A1 genotype status was an exploratory end point.

At the July 1, 2022, data cutoff, 3% of patients in the sacituzumab govitecan arm and 1% in the physician’s choice arm remained on treatment. The most common reason for treatment discontinuation was progressive disease in the sacituzumab govitecan arm (80%) and the physician’s choice arm (73%).

Among all 272 patients in the sacituzumab govitecan arm, the median age was 57.0 years (range, 29-86), 99% of patients were female, and 68% were White. Patients had an ECOG performance status of 0 (42%) or 1 (58%). Ninety-six percent of patients had metastatic disease.

Additionally, 47% of patients received 2 to 3 prior lines of chemotherapy, and 53% had more than 3 prior lines of chemotherapy. Patients were administered a median of 7.0 (range, 3-17) of prior systemic regimens. Specifically, 68%, 25%, 100%, and 3% of patients received prior systemic therapy in the adjuvant, neoadjuvant, metastatic, or other settings, respectively.

BRCA1/2 mutational status was unknown in 52% of patients. Eight percent of patients were positive for a BRCA1/2 mutation, and 40% of patients were negative.

Among evaluable White patients in the sacituzumab govitecan arm (n = 169), 39% had a wild-type UGT1A1 genotype, 45% had a heterozygous UGT1A1 genotype, and 9% had a homozygous UGT1A1 genotype. Those rates were 64%, 18%, and 0%, respectively, among Asian patients and 29%, 43%, and 14%, respectively, among Black patients.

Additional data showed that patients with wild-type, heterozygous, and homozygous UGT1A1 genotypes who received sacituzumab govitecan experienced a median relative dose intensity of 99%, 98%, and 94%, respectively. The median duration of exposure was 3.9 months, 4.8, months and 2.8 months, respectively.

Patients with homozygous UGT1A1 experienced a shorter time before onset of neutropenia and diarrhea compared with those who with a wild-type genotype. Furthermore, patients with a heterozygous genotype had a shorter time to onset of febrile neutropenia.

A longer duration of anemia was reported in patients with heterozygous UGT1A1 vs wild-type or homozygous genotypes. Duration of neutropenia, diarrhea, and febrile neutropenia was similar between the 3 groups.

Fifty-four percent of all patients included in the sacituzumab govitecan safety analysis (n = 144/268) received granulocyte colony-stimulating factor (G-CSF) for the management of neutropenia, and the median time to G-CSF initiation was 0.61 months. Forty-seven percent of patients with a wild-type UGT1A1 genotype required G-CSF with a median time to initiation of 0.69 months. Sixty percent of patients with a heterozygous UGT1A1 genotype needed G-CSF with a median time to initiation of 0.49 months, and 64% of those with a homozygous UGT1A1 genotype received G-CSF with a median time to initiation of 0.62 months.

“Active monitoring and early intervention with routine strategies for AE management [and G-CSF treatment] is recommended for all patients being treated with sacituzumab govitecan,” study authors concluded.

References

1. Marmé F, Rugo HS, Tolaney SM, et al. Safety outcomes by UGT1A1 status in the phase 3 TROPiCS-02 study of sacituzumab govitecan (SG) in HR+/HER2- metastatic breast cancer (mBC). Presented at: 2023 ESMO Breast Cancer Annual Congress; May 11-13, 2023; Berlin, Germany. Abstract 194P.
2. US FDA approves Trodelvy in pre-treated HR+/HER2- metastatic breast cancer. News release. Gilead Sciences. February 3, 2023. Accessed May 31, 2023. https://www.gilead.com/news-and-press/press-room/press-releases/2023/
3. Trodelvy. Prescribing Information. 2023. Accessed May 31, 2023. https://www.accessdata.fda.gov/drugsatfda_docs/