Sacituzumab Govitecan Succeeds in Phase III TNBC Trial, as FDA Weighs Approval

Julie R. Gralow, MD

The confirmatory phase III ASCENT study exploring sacituzumab govitecan in patients with metastatic triple-negative breast cancer (TNBC) has been stopped due to “compelling evidence of efficacy,” according to a statement from the company developing the antibody-drug conjugate (ADC), Immunomedics.¹

The company halted the trial based on a unanimous recommendation from the independent Data Safety Monitoring Committee (DSMC). The ASCENT trial was launched to confirm the positive efficacy and safety results reported in a phase II study of the ADC in TNBC.

In December 2019, the FDA accepted a biologics license application (BLA) seeking an accelerated approval for sacituzumab govitecan as a treatment for patients with metastatic TNBC who have received at least 2 prior therapies for metastatic disease.² The FDA is scheduled to decide on the BLA by June 2, 2020. An accelerated approval, which would be based on the submitted phase II data, would be contingent upon confirmatory findings, which Immunomedics will now be able to provide with the positive ASCENT results.

“It is my distinct honor to have served as Chairperson of the independent DSMC for this important study,” Julie R. Gralow, MD, Jill Bennett Endowed Professor of Breast Cancer, University of Washington School of Medicine; Member, Fred Hutchinson Cancer Research Center, stated in a press release.

“TNBC is a disease with extremely limited treatment options beyond classic chemotherapy. The remarkable results we observed across multiple endpoints in the ASCENT study warranted early discontinuation of the trial and are indicative of a potential major advance in the treatment of this devastating disease that affects younger women and African American women at higher rates. I look forward to the release of the full and final analyses of these study data when they are available for public presentation,” added Gralow.

Sacituzumab govitecan consists of the active metabolite of irinotecan, SN-38, linked with a humanized IgG antibody targeted against TROP-2, a cell-surface glycoprotein that is expressed in more than 90% of TNBC. The phase III ASCENT trial (NCT02574455) assessed sacituzumab govitecan in comparison with treatment of physician’s choice for patients with metastatic TNBC.

The median number of prior regimens was 3 (range, 2-10), which include checkpoint inhibitors for 16.7%. Additionally, 41% of patients were treated in the third-line setting and 59% were in the fourth-line or greater setting. The most common prior therapies were taxanes (98%), anthracyclines (86%), cyclophosphamide (85%), and platinum agents (75%).

In results, which were published in the New England Journal of Medicine,³ at a median follow-up of 9.7 months the objective response rate (ORR) was 33.3% by local assessment (95% CI, 24.6%-43.1%) with a median duration of response (DOR) of 7.7 months (95% CI, 4.9-10.8). The clinical benefit rate (ORR plus stable disease) was 45.4%. By blinded independent central review, the ORR was 34.3% (95% CI, 25.4%-44.0%) and the median DOR was 9.1 months (95 CI, 4.6-11.3).

The median progression-free survival (PFS) was 5.5 months (95% CI, 4.1-6.3). The estimated 6-month PFS rate 41.9%. By 12 months, the PFS rate with sacituzumab govitecan was estimated at 15.1%. The median overall survival (OS) was 13.0 months (95% CI, 11.2-13.7), with an estimated 6-month OS rate of 78.5% and a 12-month estimate of 51.3%.

Grade 3/4 adverse events (AEs) were experienced by 85% of patients receiving treatment with sacituzumab govitecan. Serious AEs were reported in 35% of patients. Overall, just 3 patients discontinued treatment due to AEs, of these 2 were deemed from study drug-related causes. Dose reductions to 7.5 mg/kg occurred in 25% of patients and the rest were able to continue sacituzumab govitecan at the 10 mg/kg dose.

The most common (≥10%) grade 3/4 AEs were neutropenia (41.7%), anemia (11%), decreased white-cell count (11%), hypophosphatemia (9%), diarrhea (8%), and fatigue and asthenia (8%). Ten patients (9.3%) developed febrile neutropenia during the course of the study. Additionally, 4 deaths occurred during treatment, and 3 patients discontinued due to AEs.

The BLA for sacituzumab govitecan was based on findings from a phase I/II study, which included 108 patients with TNBC at a median age of 55 years (range, 31-80). The majority of patients had visceral metastases (80%). Sacituzumab govitecan was administered at 10 mg/kg on days 1 and 8 of each 28-day cycle. Patients’ ECOG performance status was 0 (30%) and 1 (70%), and the median time from metastatic diagnosis to treatment in the study was 1.5 years. Overall, 57 patients had moderate (2+) to strong (3+) TROP-2 expression by immunohistochemistry and 5 had weak or absent staining for the marker. The data were not available for the remaining patients.

References

1. Immunomedics Announces ASCENT Study to be Stopped for Compelling Efficacy Published April 6, 2020. https://bit.ly/2RgJ3mu. Accessed April 6, 2020.
2. Immunomedics Announces FDA Acceptance for Filing of Biologics License Application Resubmission for Sacituzumab Govitecan to Treat Metastatic Triple-Negative Breast Cancer. Immunomedics, Inc. Published December 26, 2019. https://bit.ly/37iQ4ZD. Accessed December 27, 2019.
3. Bardia A, Mayer IA, Vahdat LT, et al. Sacituzumab govitecan-hziy in refractory metastatic triple-negative breast cancer. N Eng J Med. 2019;380:741-751. doi: 10.1056/NEJMoa1814213