“Sacituzumab govitecan induced early and durable responses in heavily pretreated patients with metastatic triple-negative breast cancer.”— Aditya Bardia, MD, MPH, and colleagues
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.
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).
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.…”
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.
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.
“Trop-2 is a novel therapeutic target, suitable for antibody-drug conjugate development.”— Francisco J. Esteva, MD, PhD
IN A SINGLE-ARM multicenter trial reported by Bardia and colleagues1 and reviewed in this issue of The ASCO Post, the use of sacituzumab govitecan...!-->!-->