FDA Approval Summary: Accelerated Approval of Sacituzumab Govitecan-hziy for Third-line Treatment of Metastatic Triple-negative Breast Cancer

Breast cancer is the most common cancer in women in the United States, with 276,000 new cases and 42,000 deaths estimated in 2020 (1). Breast cancer is rare in men, with less than 1% of cases reported in the United States. Approximately 10%–20% of all breast cancer diagnoses are triple-negative breast cancer (TNBC). This subtype is more aggressive, and is characterized by the absence of tumor expression of estrogen receptor (ER), progesterone receptor (PR), and HER2, which renders patients with TNBC unable to benefit from hormonal therapy and anti-HER2–targeted therapies (2–4). Most patients with metastatic TNBC (mTNBC) have visceral organ involvement, commonly with metastases to the brain and lungs. The estimated 5-year overall survival (OS) in patients with mTNBC is 11% (4).

Chemotherapy has been the main treatment option for patients with mTNBC, and several chemotherapy regimens may be used, however, most patients experience relapse rapidly following a response to chemotherapy. Monotherapy ixabepilone and eribulin are FDA-approved therapies for patients with metastatic breast cancer who have received at least two prior therapies in the metastatic setting (5, 6). The PARP inhibitors, olaparib and talazoparib, are more recently FDA approved, in 2018, for patients with HER2-negative breast cancer (including those with mTNBC) who harbor a germline BRCA1 or BRCA2 mutation and who have been previously treated with chemotherapy. Finally, the regimen of atezolizumab in combination with paclitaxel protein bound was approved in 2019 under the accelerated approval pathway for patients with mTNBC whose tumors express PD-L1 (PD-L1–stained tumor-infiltrating immune cells of any intensity covering ≥1% of the tumor area).

The authors provide the summary of FDA's review of the Biologics License Application (BLA) for sacituzumab govitecan-hziy (TRODELVY), which was approved for the third-line treatment of adult patients with mTNBC. Sacituzumab govitecan received FDA's breakthrough therapy designation in February 2016 for the treatment of patients with mTNBC who have received at least two prior therapies for metastatic disease. The BLA was originally submitted to the FDA in May 2018, and was granted a priority review designation. The IMMU-132-01 trial (NCT01631552) provided the primary safety and efficacy data for sacituzumab govitecan monotherapy to support the BLA. During the FDA review of the original BLA's chemistry, manufacturing, and controls (CMC) data, FDA determined that some of the data submitted to support the product quality assessment were inadequate. Specifically, the methodologies and processes used for the hRS7 antibody intermediate, IMMU-132 drug substance and drug product manufacturing, release testing, and stability testing did not provide assurance of a consistent, safe, pure, and potent product. These deficiencies served as the basis for the complete response (CR) action in January 2019. Immunomedics subsequently resubmitted the BLA in December 2019; FDA concluded that the CMC deficiencies had been satisfactorily addressed and granted accelerated approval of sacituzumab govitecan-hziy on April 22, 2020 (7, 8).

Sacituzumab govitecan is a first-in-class antibody–drug conjugate (ADC) that consists of a humanized IgG1K and anti-Trop 2 mAb (hRS7) that is covalently linked via a hydrolysable linker (CL2A) to the cytotoxic agent, SN-38, the active metabolite of irinotecan. Sacituzumab govitecan binds Trop-2 (trophoblast cell surface antigen-2) expressed on cancer cells and delivers SN-38 to the tumor upon the cleavage of CL2A linker. SN-38 interacts with topoisomerase I and prevents religation of topoisomerase I–induced single-strand breaks, ultimately resulting in apoptosis and cell death. Trop-2 antigen is expressed in a variety of epithelial cancers, and has been associated with more aggressive tumors (9). In breast cancer, Trop-2 has been found to be more commonly expressed in ER-negative, HER2-positive tumors, but less commonly expressed in patients with ER-positive, HER2-negative disease, suggesting that Trop-2 overexpression may be associated with less favorable phenotypes (9).

Treatment with sacituzumab govitecan induced proapoptotic signaling and double-strand DNA breaks in Trop-2–expressing cancer cell lines and decreased tumor growth in mouse xenograft models of TNBC (10, 11). In the acute and 13-week toxicity studies, the primary toxicologic findings in monkeys were consistent with adverse events of gastrointestinal and hematologic toxicities observed in clinical trials, and were expected on the basis of the mechanism of action of sacituzumab govitecan. Administration of sacituzumab govitecan also resulted in adverse effects on female reproductive organs in monkeys, indicating the potential for impairment of female fertility. SN-38 is genotoxic and targets rapidly dividing cells and as such, teratogenicity or embryo-fetal lethality is expected with sacituzumab govitecan. Females of reproductive potential and male patients with female partners of reproductive potential should use effective contraception during and following treatment with sacituzumab govitecan.

The proposed dosing regimen of sacituzumab govitecan is 10 mg/kg administered as an intravenous infusion on days 1 and 8 of each 21-day treatment cycle. In the IMMU-132-01 trial, escalating dose levels of sacituzumab govitecan (8, 10, 12, and 18 mg/kg i.v.) were investigated. Dose-limiting toxicity was observed at 18 mg/kg, and 12 mg/kg was declared as the MTD. Because of dose delays and dose reductions at the 12 mg/kg dose, lower doses (8 and 10 mg/kg) were chosen for further investigation. The dose expansion portion of the IMMU-132-01 trial investigated sacituzumab govitecan in patients with various solid tumors who received the 8 (n = 81) and 10 mg/kg (n = 97) doses. While the safety profiles of the two investigated dose levels appeared comparable, the observed response rate was numerically higher at the 10 mg/kg dose compared with the 8 mg/kg dose, and, thus, the 10 mg/kg dose was selected for further clinical development (12). No dose adjustments were required for patients with renal impairment or mild hepatic impairment. However, an adequate starting dose in patients with moderate hepatic impairment is unknown. The FDA requested a safety and pharmacokinetics study in patients with moderate hepatic impairment to determine the adequate starting dose, as a postmarketing requirement (PMR).

Uridine diphosphate-glucuronosyltransferase 1A1 (UGT1A1) is involved in the metabolism of SN-38 to SN-glucuronide, and concomitant administration of drugs that alter UGT1A1 activity should be avoided to minimize the potential for increased frequency and severity of adverse reactions (13). In addition, patients homozygous for the UGT1A1*28 allele are at an increased risk for adverse reactions, especially neutropenia; the appropriate dose in these patients is not known. Given the concern regarding the UGT1A1 genotype and increased risk of toxicities, a PMR was agreed upon, which will further characterize the impact of UGT1A1 variants and toxicity. In addition, labeling included information cautioning use in patients homozygous for the UGT1A1*28 allele. The observed unconjugated SN-38 concentrations with the approved dose of sacituzumab govitecan were present at substantially higher concentrations compared with the SN-38 concentrations observed with the highest approved dose of irinotecan, and the potential for QT interval prolongation cannot be ruled out at such a high exposure of SN-38. Another study to evaluate the risk of QT prolongation with sacituzumab govitecan therapy will be conducted as a PMR.

IMMU-132-01 (NCT01631552) is a single-arm, open-label, dose escalation and dose expansion, multicenter (U.S. only) phase I/II trial of sacituzumab govitecan in patients with advanced solid tumors (14). The dose escalation portion of the trial employed a 3+3 design to evaluate escalating doses of sacituzumab govitecan. The dose expansion portion of the trial enrolled patients into four single-arm cohorts, one of which enrolled patients with mTNBC. The primary endpoint of the dose expansion portion of the trial was confirmed objective response rate (ORR) according to the RECIST version 1.1 guidelines, as assessed by the investigator. Duration of response (DoR) was a secondary endpoint. Sacituzumab govitecan was administered at doses of 8 and 10 mg/kg until evidence of disease progression or unacceptable toxicities.

Originally submitted to the FDA in May 2018, the efficacy analysis set for this approval consisted of the 108 patients with mTNBC enrolled in the dose escalation and dose expansion portion of IMMU-132-01 trial who had received at least two prior lines of therapy in the metastatic setting, and who have received sacituzumab govitecan at 10 mg/kg dose via intravenous infusion on days 1 and 8 of continuous 21-day cycles, at the time of the initial data cutoff of 30 June 2017. The safety analysis set included the 408 patients with various solid tumors in the IMMU-132-01 trial who had received at least one dose of sacituzumab govitecan, including the subgroup of 108 patients with mTNBC who comprised the efficacy set.

The baseline demographics of the mTNBC patient population (N = 108) were as follows: median age, 55 years (range, 31–80); 99% female; 76% White; 29% and 71% with an Eastern Cooperative Oncology Group performance status of 0 and 1, respectively; 76% with visceral disease; and 2% with brain metastases. At baseline, 60% of patients had received two prior chemotherapies and 40% had received three or more prior chemotherapies in the metastatic setting; all patients had measurable disease.

The efficacy results for the mTNBC patient cohort of IMMU-132-01 trial are summarized in Table 1. Sacituzumab govitecan at the 10 mg/kg i.v. dose demonstrated an ORR of 33.3% [95% confidence interval (CI), 24.6%–43.1%] consisting of three CRs (2.8%) and 33 partial responses (PR, 30.6%), according to RECIST v1.1, at the initial data cutoff of 30 June 2017. The median DoR was 7.7 months (95% CI, 4.9–10.8) on the basis of an updated data cutoff of 1 December 2017. Fifty-six percent of responders had a DoR ≥ 6 months and 17% had a DoR ≥ 12 months. Blinded, independent review of a subgroup of patients (n = 55) who had CR, PR, or at least 20% shrinkage by investigator assessment was consistent with the investigator assessment.

The safety profile of sacituzumab govitecan was assessed in the overall study population in IMMU-132-01 trial who received sacituzumab govitecan at doses up to 10 mg/kg (N = 408), and in the subset of patients who comprised the efficacy mTNBC population (N = 108). In the mTNBC population, the median exposure to sacituzumab govitecan was 5.1 months, and no deaths within 30 days of ending study treatment were associated with study therapy. Dose interruptions and dose reductions due to adverse reactions were reported in 45% and 33% of patients, respectively. The most common adverse reactions leading to dose interruptions and dose reductions were neutropenia/febrile neutropenia. Treatment discontinuation due to adverse reactions was reported in 2% of patients. Adverse reactions leading to discontinuation were anaphylaxis, anorexia/fatigue, and headache.

Serious adverse reactions (SAR) were reported in 31% of the patients. The most common SARs (i.e., occurring in >1% of patients) were febrile neutropenia (6%), vomiting (5%), nausea (3%), dyspnea (3%), diarrhea (4%), anemia (2%), and pleural effusion, neutropenia, pneumonia, and dehydration (each 2%). Grade 3–4 adverse reactions were observed in 72% of patients. The most common grade 3–4 adverse reactions (i.e., occurring in ≥5% of patients) by preferred term were neutropenia (43%), anemia (12%), diarrhea and hypophosphatemia (9% each), fatigue and febrile neutropenia (8%, each), vomiting (6%), and dehydration (5%). Among the 84% (343/408) of patients who received sacituzumab govitecan (up to 10 mg/kg dose), and had retrospective UGT1A1 genotype results available, the incidence of grade 4 neutropenia was 26% (10/39) in patients homozygous for the UGT1A1*28 allele, 13% (20/155) in patients heterozygous for the UGT1A1*28 allele, and 11% (16/149) in patients homozygous for the wild-type allele. Patients with known reduced UGT1A1 activity should be monitored for severe neutropenia.

The most common all-grade adverse reactions (≥25% in incidence: nausea, neutropenia, diarrhea, fatigue, anemia, vomiting, alopecia, constipation, rash, decreased appetite, and abdominal pain) were manageable with monitoring, dose modifications, and supportive measures.

The FDA's accelerated approval of sacituzumab govitecan on April 22, 2020 was the first approval for sacituzumab govitecan worldwide. It is also the first ADC approved by the FDA specifically for mTNBC. Patients living with mTNBC have limited treatment options and urgently need new safe and effective therapies, particularly for patients who are heavily pretreated, as was the case in patients enrolled in the IMMU-132-01 trial. This approval addresses this unmet medical need. Some of the limitations of the trial include the enrollment of a limited number (2%) of patients who had brain metastases at baseline, and despite the disproportionate representation of African American women among cases of mTNBC, only 7% of the patients in the trial were Black. While the demographics of the mTNBC patient population in the IMMU-132-01 trial were generally consistent with the U.S. population that would be eligible to receive sacituzumab govitecan treatment, Blacks were underrepresented in the IMMU-132-01 trial relative to their representation among cases of the disease (15–17). This finding has also been observed in other recent trials supporting the approval of drugs intended for the treatment of patients with breast cancer, with the proportion of Black or African American patients enrolled ranging between 2.2% and 8.9% of the study population (18–20). Given that approximately 20% of the Black or African American population, compared with 10% of the White population, are homozygous for the UGT1A1*28 allele, additional information obtained with the PMR will be particularly important to understand use in this population. In addition, further measures to improve enrollment of this demographic subgroup in clinical trials are needed.

ORR is a commonly used regulatory endpoint in oncology as it is directly attributable to the drug activity. Tumor measurements are relevant for clinical decision-making and can be supported by DoR. ORR with supportive DoR, which allow for smaller sample sizes and study in single-arm trials, is most frequently used for accelerated approval. Accelerated approval requires a drug to be better than available therapies with an endpoint earlier then survival that is reasonably likely to predict clinical benefit. The two FDA-approved agents for third and later lines of therapy in the metastatic breast cancer space are eribulin and ixabepilone. The ORR of sacituzumab govitecan was clearly improved above that of ixabepilone (12.4%; 95% CI, 6.9–19.9; median DoR, 6 months) and eribulin (11%; 95% CI, 8.6–14.3; median DoR, 4.2 months). The FDA risk–benefit analysis is shown in Table 2 (8). Sacituzumab govitecan's improvement in ORR and DoR over available therapy, coupled with the acceptable safety profile, supported the use of the accelerated approval pathway for sacituzumab govitecan; at the time of approval, the ongoing confirmatory trial was underway to confirm clinical benefit. ASCENT (NCT02574455) is a randomized, open-label, phase III trial of sacituzumab govitecan versus treatment of physician's choice (TPC) in patients with mTNBC after ≥2 prior chemotherapies for advanced disease or >1 therapy for patients who progressed within 12 months of adjuvant therapy. This study was designed under an FDA special protocol assessment indicating concurrence by FDA with the adequacy and acceptability of specific critical elements of overall protocol design (e.g., entry criteria, dose selection, endpoints, and planned analyses) for a study intended to support a future marketing application (21). Patients were randomized 1:1 to receive either sacituzumab govitecan or TPC. The primary endpoint was progression-free survival (PFS) as assessed by blinded, independent review. Secondary endpoints include OS, ORR, DOR, safety, and quality of life. On 6 April 2020, it was reported that ASCENT was a positive study with subsequent results reported as demonstrating an improvement in PFS, OS, and ORR with sacituzumab govitecan (22).

mTNBC is an aggressive phenotype of breast cancer; patients who have received two prior therapies for metastatic disease have an advanced condition that is life-threatening and have an unmet medical need. Results from the IMMU-132-01 trial demonstrated a favorable benefit–risk profile for sacituzumab govitecan with an improved ORR and DoR over available therapies. The most common adverse reactions associated with sacituzumab govitecan therapy were nausea, neutropenia, diarrhea, fatigue, anemia, vomiting, alopecia, constipation, rash, decreased appetite, and abdominal pain. These adverse reactions are acceptable with monitoring, dose modifications, and supportive measures. Overall, sacituzumab govitecan exhibited a favorable benefit–risk profile and met criteria for accelerated approval, resulting in a new targeted therapy for the treatment of an aggressive malignancy that affects younger patients and for whom available treatment options are very limited.

No disclosures were reported.

The Editor handling the peer review and decision-making process for this article has no relevant employment associations to disclose.