Immunotherapy & Sacituzumab Govetecan Are Promising Advances for TNBC Treatment
by C.H. Weaver M.D. 7/11/2018
Approximately 12% of breast cancers are triple-negative breast cancers (TNBC), meaning that they are estrogen-receptor negative (ER-), progesterone-receptor negative (PR-), and human epidermal growth factor receptor 2-negative (HER2-). This means that TNBC is not stimulated to grow from exposure to the female hormones estrogen or progesterone, nor through an overactive HER2 pathway.
Unfortunately, many available and effective treatment options for the majority of breast cancers block the growth stimulating effects of ER, PR and/or HER2; therefore, TNBC has limited therapeutic options. Novel treatment options for TNBC have lagged behind that of other types of breast cancers.
TNBC tends to be more aggressive and grow at a rapid rate. There are two major challenges in treating TNBC: First, because they have no known targets (such as estrogen receptor or HER2/neu), currently the only way to treat them is to use chemotherapy, which generally results in more side effects. Second, even when we treated with chemotherapy the response is often short lived.
There are no modifiable risk factors for triple-negative breast cancer. These cancers tend to occur more frequently in young premenopausal women, in African-American women, and in women who carry the abnormal inherited breast cancer susceptibility gene BRCA1.
The standard protocol to treat early-stage TNBC confined to the breast and axillary lymph nodes is chemotherapy and surgery. Often chemotherapy is administered before surgery.
Individuals diagnosed with TNBC should ask their doctor whether there is an appropriate clinical trial in which they could participate. Novel approaches to the treatment of TNBC are being investigated. It is important that patients make use of these opportunities when possible to increase their treatment options. In addition, patients should be sure to consult their healthcare team to see if genetic testing should be a consideration.1
Strategies To Improve Treatment of TNBC
The development of more effective cancer treatments requires that new and innovative therapies be evaluated with cancer patients. Clinical trials are studies that evaluate the effectiveness of new drugs or treatment strategies. Participation in a clinical trial may offer patients access to better treatments and advance the existing knowledge about treatment of this cancer. Areas of active investigation aimed at improving the treatment of TNBC include the following:
Immunotherapy with Checkpoint Inhibitors
Checkpoint inhibitors are a novel precision cancer immunotherapy that helps to restore the body’s immune system in fighting cancer. They create their anti-cancer effects by blocking a specific protein used by cancer cells called PD-1 and PD-L1 to escape an attack by the immune system. Once PD-L1 is blocked, cells of the immune system are able to identify cancer cells as a threat, and initiate an attack to destroy the cancer. There are several PD-1 and PD-L1 inhibitors already approved for use to treat multiple cancer types.
Recently at the American Society of Clinical Oncology meetings additional evidence on the role of Keytruda (pembrolizumab), a checkpoint inhibitor was presented. In the KEYNOTE-086 clinical trial patients with previously treated metastatic TNBC had prolonged and durable response rates. Patients with previously untreated PD-L1 positive metastatic TNBC experienced an overall response rate of 23%.3
In a second clinical trial (I-SPY2) combining Keytruda with Taxol (paclitaxel) in newly diagnosed, high-risk TNBC patients, a pathologic complete response rate of 60% in the neoadjuvant setting was observed and, compared favorably with the 20% response rate observed with chemotherapy alone.1
Another checkpoint inhibitor Tecentriq (Atezolizumab) has also demonstrated early encouraging results. Among patients with metastatic TNBC; those who responded to Tecentriq lived significantly longer compared with those who did not respond, according to data from a small clinical study presented at the American Association of Cancer Research annual meeting.2
Taken together, these studies suggest that checkpoint inhibitors are active against TNBC. Doctors will continue to evaluate how best to incorporate these novel precision cancer medicines into their overall treatment strategy.
The antibody drug conjugate sacituzumab govetecan (IMMU-132) has received Breakthrough Therapy Designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with triple-negative breast cancer (TNBC).
Sacituzumab govitecan targets Trop-2, a calcium signal transducer that drives cancer cell growth in a majority of TNBC patients. IMMU-132 delivers high doses of SN-38, the active metabolite of Irinotecan that is 1000 times more active than Irinotecan itself.
In this early study IMMU-132 was well tolerated and produced an overall response rate of 30% in patients that had failed an average of 5 previous therapies. Additionally, 45% of patients had stable disease (SD), with 16% of the responses lasting for greater than 6 months.6
- Schmid P, Cruz C, Braiteh FS, et al: Atezolizumab in metastatic TNBC: Long-term clinical outcomes and biomarker analysis. 2017 AACR Annual Meeting. Abstract 2986. Presented April 3, 2017.
- Bardia A, Diamond JR, Mayer IA, et al. Sacituzumab govitecan (IMMU-132), an anti-Trop-2-SN-38 antibody-drug conjugate (ADC) for the treatment of relapsed/refractory, metastatic triple-negative breast cancer (mTNBC): Updated results. Presented at: 2016 San Antonio Breast Cancer