Novel Antibody-Drug Conjugate Active in Refractory Triple-Negative Breast Cancer


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In relapsed or refractory triple-negative breast cancer, the antibody-drug conjugate sacituzumab govitecan (IMMU-132) demonstrated significant clinical activity in an open-label study presented at the 2017 San Antonio Breast Cancer Symposium.1

“Metastatic triple-negative breast cancer is an aggressive disease with a poor prognosis that tends to affect young women,” said Aditya Bardia, MD, MPH, Director of Precision Medicine at the Center for Breast Cancer, Massachusetts General Hospital, Harvard Medical School, Boston. “Currently, there is no single standard chemotherapy available for relapsed or refractory disease. The response rates to standard chemotherapy are low, and the median progression-free survival is in the range of 2 or 3 months with standard therapy such as capecitabine, cisplatin or carboplatin, eribulin (Halaven), or nab-paclitaxel (Abraxane). Consequently, there is a large unmet need in the breast cancer community.”


Sacituzumab govitecan as a single agent demonstrated significant clinical activity as a third-line and beyond therapy in patients with relapsed or refractory metastatic triple-negative breast cancer.
— Aditya Bardia, MD, MPH

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In San Antonio, Dr. Bardia presented efficacy results related to sacituzumab govitecan as third-line treatment or beyond for metastatic triple-negative breast cancer. The conjugate consists of SN-38, the active metabolite of irinotecan, linked with a humanized immunoglobulin G antibody targeted against Trop-2, a cell-surface glycoprotein expressed on more than 90% of triple-negative tumors. “The payload, SN-38, is more potent than the parent compound irinotecan, and the antibody-drug conjugate delivers up to 136 times more SN-38 than irinotecan in vivo,” he noted.

Because of the need for more effective drugs for advanced triple-negative cancers, sacituzumab govitecan received Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA) for patients with triple-negative disease that has progressed after at least two regimens.

Key Findings

The preliminary results in 69 patients with metastatic triple-negative breast cancer previously showed an objective response rate of 30%, which was published earlier in the Journal of Clinical Oncology.2 In 2016, sacituzumab govitecan was awarded Breakthrough Therapy designation by the FDA, and enrollment was resumed in a more defined population in the third-line or later setting. The single-arm open-label study included 110 patients (median age, 55 years) who were treated with 10 mg/kg of the drug on days 1 and 8 every 21 days, in the third-line (41%) or fourth-line setting or beyond (59%), until disease progression or unacceptable toxicity. They received a median of 14.5 doses over a median of 4.9 months.

A total of 66 patients died, 30 patients remain in long-term follow-up, and 14 patients remain on treatment. The objective response rate was 34% by local assessment, including 3 complete responses and 34 partial responses, and 31% by blinded independent review, including 6 complete and 28 partial responses. The clinical benefit rate at 24 weeks was 45%, and response rates did not vary according to age, prior regimens, or onset of metastatic disease. There were 19 patients who had received a checkpoint inhibitor, and 9 of them (47%) responded to sacituzumab govitecan, Dr. Bardia reported.

NOVEL AGENT FOR TRIPLE-NEGATIVE BREAST CANCER

  • The antibody-drug conjugate sacituzumab govitecan was evaluated as a third-line and beyond therapy option in a single-arm phase II study of 110 patients with relapsed or refractory triple-negative breast cancer.
  • The response rate was 30%, median progression-free survival was 5.5 months, and median overall survival was
    12.7 months.
  • The drug is moving forward into a phase III trial, also in the third-line and beyond setting.

The median duration of response was 7.6 months according to local assessment and 9.1 months by central review, with a median time to response of 2 months. Nine long-term responders remained free of disease progression for at least 1 year after starting therapy. Median progression-free survival was 5.5 months, and median overall survival was 12.7 months, he said.

Neutropenia was reported in 63% of patients and was grade 3/4 in 41%, although it was associated with fever in only 7%. Adverse events were managed sufficiently with supportive care and dose reductions. Two patients (1.8%) discontinued treatment due to adverse events, including a grade 3 transient infusion reaction and grade 2 fatigue.

“Sacituzumab govitecan as a single agent demonstrated significant clinical activity as a third-line and beyond therapy in patients with relapsed or refractory metastatic triple-negative breast cancer,” Dr. Bardia concluded. “Results demonstrate that sacituzumab govitecan has a predictable and manageable safety profile.”

The confirmatory phase III ASCENT trial is currently recruiting patients globally who have received at least two prior regimens or at least one regimen if disease progressed within 12 months of completing neoadjuvant or adjuvant therapy. Target enrollment is 328 patients, and sacituzumab govitecan will be compared with the treatment of physician choice. Additional studies of this agent in combination with other drugs are currently being evaluated in metastatic triple-negative and other breast cancer subsets. ■

DISCLOSURE: Dr. Bardia reported no conflicts of interest.

REFERENCE

1. Bardia A, Vahdat LT, Diamond J, et al: Sacituzumab govitan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate, as ≥ 3rd-line therapeutic option for patients with relapsed/refractory metastatic triple-negative breast cancer: Efficacy results. 2017 San Antonio Breast Cancer Symposium. Abstract GS1-07. Presented December 6, 2017.

2. Bardia A, Mayer IA, Diamond JR, 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.


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