On April 22, 2020, the antibody-drug conjugate sacituzumab govitecan-hziy was granted accelerated approval for treatment of adult patients with metastatic triple-negative breast cancer who have received at least two prior therapies for metastatic disease.^1,2

Supporting Efficacy Data

Approval was based on findings in the phase I/II multicenter IMMU-132-01 trial (ClinicalTrials.gov identifier NCT01631552).^2,3 In the trial, 108 patients with metastatic triple-negative breast cancer who received at least two prior treatments for metastatic disease received sacituzumab govitecan-hziy, 10 mg/kg intravenously, on days 1 and 8 every 21 days, with treatment continuing until disease progression or unacceptable toxicity. Patients with bulky disease, defined as a mass > 7 cm, were not eligible for the trial.

The median age of study patients was 55 years (range = 31–80 years; 87% < 65 years), 99% were female, 76% were white, and Eastern Cooperative Oncology Group performance status was 0 (29%) or 1 (71%) in all patients. Overall, 76% had visceral disease, 42% had hepatic metastases, 56% had lung/pleura metastases, 2% had brain metastases, and 12% had stage IV disease. The median number of prior systemic therapies in the metastatic setting was three (range = 2–10), with prior treatment including 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% prior anthracyclines in the (neo)adjuvant or metastatic setting.

Objective response was achieved in 36 patients (33.3%, 95% confidence interval = 24.6%–43.1%), with a complete response in 3 patients (2.8%). Median response duration was 7.7 months (range = 1.9+ to 30.4+ months), with response ≥ 6 months in 55.6% and ≥ 12 months in 16.7%.

How It Works

Sacituzumab govitecan-hziy is a Trop-2–directed antibody-drug conjugate. Sacituzumab is a humanized antibody that recognizes Trop-2. The attached small molecule SN-38 is a topoisomerase I inhibitor covalently bound to the antibody by a linker.

Sacituzumab govitecan-hziy binds to Trop-2–expressing cancer cells and is internalized, with subsequent release of SN-38 via hydrolysis of the linker. SN-38 interacts with topoisomerase I and prevents re-ligation of topoisomerase I–induced single-strand breaks. The resulting DNA damage leads to apoptosis and cell death. Sacituzumab govitecan-hziy decreased tumor growth in mouse xenograft models of triple-negative breast cancer.

How It Is Used

Sacituzumab govitecan-hziy must not be substituted for or used with other drugs containing irinotecan or its active metabolite SN-38.

The recommended dose of sacituzumab govitecan-hziy is 10 mg/kg via intravenous infusion once weekly on days 1 and 8 of 21-day cycles, with treatment continuing until disease progression or unacceptable toxicity. Doses greater than 10 mg/kg should not be administered.

Prior to each dose, premedication is recommended for prevention of infusion reactions (antipyretics, H1 and H2 blockers; corticosteroids may be used in patients with prior infusion reactions) and for prevention of chemotherapy-induced nausea and vomiting (two- or three-drug combinations—eg, dexamethasone with either a 5-HT3 receptor antagonist or an NK1 receptor antagonist, as well as other drugs as indicated). The first infusion should be given over 3 hours while monitoring the patient for reactions during the infusion and for 30 minutes afterward. Subsequent infusions can be administered over 1 to 2 hours if the prior infusion was tolerated. Infusion should be interrupted or slowed for reactions, and treatment must be permanently discontinued for life-threatening reactions.

Prescribing information provides instructions for dose modification—including 25% and 50% reductions—for adverse events such as severe neutropenia and severe non-neutropenic toxicity, including diarrhea. The dose of sacituzumab govitecan-hziy should not be re-escalated after any dose reduction. Concomitant use with UGT1A1 inhibitors or inducers should be avoided.

Safety Profile

Among the 108 patients in the IMMU-132-01 trial, median treatment duration was 5.1 months (range = 0–51 months).

The most common adverse events of any grade (≥ 25% of patients) were nausea (69%), neutropenia (64%), diarrhea (63%), fatigue (57%), anemia (52%), vomiting (49%), alopecia (38%), constipation (34%), rash (31%), decreased appetite (30%), and abdominal pain (26%). Grade 3 or 4 adverse events occurred in 71% of patients, with the most common being neutropenia (43%), anemia (12%), diarrhea (9%), hypophosphatemia (9%), fatigue (8%), nausea (6%), and vomiting (6%). The most common grade 3 or 4 laboratory abnormalities were decreased neutrophils (32%), decreased leukocytes (26%), increased activated partial thromboplastin time (12%), and deceased hemoglobin (6%).

Serious adverse events occurred in 31% of patients, with the most common being febrile neutropenia (6%), vomiting (5%), nausea (3%), dyspnea (3%), diarrhea (4%), anemia (2%), pleural effusion (2%), neutropenia (2%), pneumonia (2%), and dehydration (2%). Adverse events led to treatment interruption in 45% of patients, with the most common cause being neutropenia (33%), and to dose reduction in 33% (24% with one and 9% with two reductions), with the most common cause being neutropenia/febrile neutropenia. Other adverse events resulted in permanent discontinuation of treatment in 2% of patients, with causes consisting of anaphylaxis, anorexia/fatigue, and headache in one patient each.

Among 408 patients with metastatic triple-negative breast cancer and other malignancies receiving single-agent sacituzumab govitecan-hziy, hypersensitivity reactions within 24 hours of dosing occurred in 37%, with grade 3 or 4 reactions occurring in 1%.

Sacituzumab govitecan-hziy has boxed warnings for severe neutropenia and severe diarrhea. Treatment should be withheld for an absolute neutrophil count below 1,500/mm³ or neutropenic fever. Blood cell counts should be monitored periodically during treatment, and granulocyte colony-stimulating factor should be considered for secondary prophylaxis. Anti-infective treatment for febrile neutropenia should be initiated without delay. Patients with diarrhea should be monitored and given fluid and electrolytes as needed. If not contraindicated, atropine should be given for early diarrhea of any severity. At the onset of late diarrhea, patients should be evaluated for infectious causes and, if negative, should receive prompt initiation of loperamide. If severe diarrhea occurs, treatment should be withheld until resolution to ≤ grade 1, followed by a reduction in subsequent doses.

Sacituzumab govitecan-hziy also has warnings/precautions for hypersensitivity reactions, including severe anaphylactic reactions; nausea/vomiting; patients with reduced UGT1A1 activity; and embryofetal toxicity. Treatment should be withheld for patients with grade 3 nausea or grade 3 or 4 vomiting at the time of scheduled treatment. Individuals who are homozygous for the UGT1A1*28 allele are at increased risk for neutropenia following initiation of treatment.

Patients should be advised not to breastfeed while receiving sacituzumab govitecan-hziy, which is also contraindicated in patients with a severe hypersensitivity reaction to the agent. 

REFERENCES

1. U.S. Food and Drug Administration: FDA grants accelerated approval to sacituzumab govitecan-hziy for metastatic triple negative breast cancer. Available at https://www.fda.gov/drugs/drug-approvals-and-databases/fda-grants-accelerated-approval-sacituzumab-govitecan-hziy-metastatic-triple-negative-breast-cancer. Accessed May 6, 2020.

2. U.S. Food and Drug Administration: Highlights of prescribing information for Trodelvy (sacituzumab govitecan-hziy) for injection. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/761115s000lbl.pdf. Accessed May 6, 2020.

3. Bardia A, Mayer IA, Vahdat LT, et al: Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Engl J Med 380:741-751, 2019.