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Novel Antibody-Drug Conjugate Targets Triple-Negative Breast Cancer


The antibody-drug conjugate sacituzumab govitecan (IMMU-132) produced high objective response rates, many of them quite durable, in a multicenter study of heavily pretreated patients with metastatic triple-negative breast cancer, presented at the 2016 San Antonio Breast Cancer Symposium.1

Trop-2 is a calcium signal transducer that drives tumor growth and has shown promise as a novel therapeutic target in triple-negative breast cancer, since the majority of these tumors express Trop-2. Sacituzumab govitecan targets Trop-2 and selectively delivers high doses of SN-38, the active metabolite of irinotecan that is 1,000 times more active than the parent compound. In addition to drug delivery, sacituzumab govitecan potentially also activates antibody-dependent cell-mediated cytotoxicity.


Approximately one-third of patients with relapsed/refractory triple-negative breast cancer had confirmed responses.
— Aditya ­Bardia, MD, MPH

“Approximately one-third of patients with relapsed/refractory triple-negative breast cancer had confirmed responses, including two complete responses as well as a partial response in a patient whose tumor did not respond to anti–PD-L1 [programmed cell death ligand 1] therapy,” said ­Aditya ­Bardia, MD, MPH, attending physician at Massachusetts General Hospital Cancer Center and Assistant Professor at Harvard Medical School, Boston, who presented the findings at the meeting.

He noted that sacituzumab govitecan was well tolerated and induced early and durable responses. The median progression-free survival was 6.0 months, and median overall survival was 16.6 months.

Sacituzumab govitecan has received Breakthrough Therapy status for treatment of patients with triple-negative breast cancer. The drug is also being evaluated in non–small cell lung cancer, small cell lung cancer, and bladder cancer, where it has produced encouraging results as well, Dr. Bardia told The ASCO Post.

Key Findings

The study included 69 patients with metastatic triple-negative breast cancer who received sacituzumab govitecan at 10 mg/kg on days 1 and 8 every 21 days. Trop-2 expression was not required for enrollment, but tumor specimens were stained for Trop-2 by immunohistologic assay, and 89% were found to be moderately to strongly positive for Trop-2.

The average patient received 14 doses over about 5 months. After a median follow-up of almost 17 months, 62 patients had discontinued treatment, whereas 7 patients were still on treatment.

In this relapsed/refractory population—in which patients had received a median of five prior therapies—the objective response rate was 30%, with 2 confirmed complete responses (3%) and 19 partial responses (28%), and stable disease was observed in 31 ­patients (45%).

Sacituzumab Govitecan in Triple-Negative Breast Cancer

  • A multicenter study evaluated the antibody-drug conjugate sacituzumab govitecan in 69 patients with relapsed/refractory metastatic triple-negative breast cancer. The drug targets Trop-2.
  • The drug produced responses in 30% of patients, including 2 complete responses. Tumor shrinkage was observed in a patient whose disease progressed on checkpoint inhibitors.
  • Sacituzumab govitecan has received Breakthrough Therapy status for the treatment of patients with triple-negative breast cancer.

Most responses occurred early, usually within 2 months, and lasted about 9 months. The duration of response in the 21 confirmed responders was 8.9 months. At data cutoff, 14 had disease progression and discontinued treatment, whereas 6 continued to respond to treatment (3 with ongoing long-term responses at 13 to 21 months); one received radiation after 12 months for new brain lesions and is currently continuing treatment, with additional shrinkage of body lesions. In one patient who had received four prior lines of therapy, including anti–PD-L1 therapy, tumor reduction of 54% was noted with sacituzumab therapy.

Dr. Bardia commented that the 30% response rate, and especially the 2 complete responses, “are very encouraging for a single agent in triple-negative disease.” While cautioning the results are not from a randomized trial, he noted that both the response rate and the 6-month median progression-free survival are approximately double those historically achieved with standard chemotherapy in heavily pretreated patients with triple-negative breast cancer.

Grade ≥ 3 adverse events were observed in 41% of patients, the most common being neutropenia (39%), leukopenia (16%), anemia (14%), diarrhea (13%), and vomiting (10%). Febrile neutropenia was limited to 7%. Three patients discontinued treatment due to adverse events after six or seven doses (for grade 3 rash/mucositis, grade 3 transient infusion reaction, grade 2 fatigue). No patient developed neutralizing antibodies.

“Given the aggressive tumor biology and high mortality associated with metastatic triple-negative breast cancer, there is a need for better therapies, and the findings of this study support the development of this therapeutic drug in a patient population with an unmet medical need,” Dr. Bardia concluded. ■

Disclosure: Dr. Bardia reported no potential conflicts of interest.

Reference

1. Bardia A, Diamond JR, Mayer IA, et al: Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate for the treatment of relapsed/refractory, metastatic triple-negative breast cancer: Updated results. 2016 San Antonio Breast Cancer Symposium. Abstract P4-22-15. Presented December 9, 2016.


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I think we will see improvements with these drugs and hope that antibody-drug conjugates will be the future of chemotherapy.
— Howard A. “Skip” Burris, MD

Howard A. “Skip” Burris, MD, President of Clinical Operations and Chief Medical Officer at Sarah Cannon Research...


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