“Sacituzumab govitecan induced early and durable responses in heavily pretreated patients with metastatic triple-negative breast cancer.”

— Aditya Bardia, MD, MPH, and colleagues

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AS REPORTED in the Journal of Clinical Oncology by Aditya Bardia, MD, MPH, of Massachusetts General Hospital Cancer Center and Harvard Medical School, and colleagues, the anti–Trop-2 antibody-drug conjugate sacituzumab govitecan has been found to produce durable responses in patients with heavily pretreated metastatic triple-negative breast cancer.¹ 

Trop-2, a glycoprotein initially identified in a trophoblast cancer cell line, is overexpressed in various solid cancers, including triple-negative breast cancer, and has been shown to have oncogenic properties; overexpression of Trop-2 has been correlated with poor prognosis in several cancers, including breast cancer. Sacituzumab govitecan consists of the anti–Trop-2 antibody sacituzumab and govitecan, the active metabolite of irinotecan, which has a 100-fold to 1,000-fold greater potency than the parent compound and contributes to irinotecan toxicity. The antibody-drug conjugate is aimed at selective delivery of higher levels of govitecan to tumors. 

Study Details 

THE CURRENT REPORT includes all 69 patients (1 male) with metastatic triple-negative breast cancer treated in a phase I/II study who received sacituzumab govitecan at the 10-mg/kg dose level selected for further clinical development. Patients received 10 mg/kg on days 1 and 8 of repeated 21-day cycles. The primary outcome measures were response rate and safety. 

Patients had a median age of 56 years; 83% were white; all had an Eastern Cooperative Oncology Group performance status of 0 or 1; the stage at diagnosis was I in 17%, II in 36%, III in 30%, and IV in 14%; the median number of prior therapies was 5 (range = 1–12), including taxanes in 97%, cyclophosphamide in 91%, anthracyclines in 84%, and platinum agents in 70%. 

As of the data cutoff in August 2016, with a median follow-up of 16.6 months, 62 patients had discontinued treatment and 7 remained on therapy. Patients received a median of 14 doses, with a median duration of exposure of 5.3 months. Most patients received premedication to avoid infusion reactions. 

An objective response was observed in 21 patients (30%, 95% confidence interval = 20%–43%), including a partial response in 19 patients and a complete response in 2 patients. The median time to response was 1.9 months, and the median duration of response was 8.9 months (95% CI = 6.1–11.3 months). Stable disease was observed in 31 patients (45%). The clinical benefit rate (objective response plus stable disease for ≥ 6 months) was 46%. Median progression-free survival was 6.0 months (95% CI = 5.0–7.3 months), and median overall survival was 16.6 months (95% CI = 11.1–20.6 months). 

Trop-2 Expression 

ASSESSMENT FOR Trop-2 expression was performed by immunohistochemistry in 48 patients with archival tumors (60% primary tumors, 40% miscellaneous metastases). Of them, 42 patients (88%) had moderate (2+) to strong (3+) Trop-2 staining, with the majority expressing Trop-2 in more than 50% of tumor cells; 6 patients (12%) had weak (1+; n = 4) or no (n = 2) Trop-2 staining. 

Among the 46 patients evaluable for response, all 16 responders had moderate to strong Trop-2 staining, whereas stable disease was the best response among those with weak or no Trop-2 staining. Among all 48 patients, there was a trend toward prolonged progression-free survival for moderate to strong vs weak or no staining (median = 7.1 vs 3.1 months, P = .019). 

Four patients had previously received anti–programmed cell death ligand 1 (PD-L1) antibody treatment, with one having a response of 4 months in duration. Three of these patients achieved partial response on sacituzumab govitecan. The investigators noted: “This anecdotal observation suggests that the [antibody-drug conjugate] and programmed cell death protein 1 (PD-1)/PD-L1 antibodies represent non–cross-resistant therapeutic options for a potential combination therapy.…” 

Adverse Events 

GRADE ≥ 3 adverse events occurred in 41% of patients, with the most common being neutropenia (39%), leukopenia (16%), anemia (14%), diarrhea (13%), and vomiting (10%). Grade 3 febrile neutropenia occurred in 7%. Adverse events, primarily neutropenia, led to dose reduction in 19% of patients during the first two cycles of treatment. Treatment was discontinued in three patients after six to seven doses, due to grade 3 rash/mucositis, grade 3 transient infusion reaction, and grade 2 fatigue. No treatment-related deaths were observed. No neutralizing antibodies to the conjugate or the antibody were observed. 

The investigators concluded: “Sacituzumab govitecan was well tolerated and induced early and durable responses in heavily pretreated patients with metastatic triple-negative breast cancer. As a therapeutic target and predictive biomarker, Trop-2 warrants further research.” ■ 

DISCLOSURE: The study was supported by Immunomedics. For full disclosures of the study authors, visit www.jco.ascopubs.org. 

REFERENCE 

1. Bardia A, et al: Efficacy and safety of anti-Trop-2 antibody drug conjugate sacituzumab govitecan (IMMU-132) in heavily pretreated patients with metastatic triple-negative breast cancer. J Clin Oncol 35:2141-2148, 2017.