Big Changes Coming in Treatment of Triple-Negative Breast Cancer

The treatment paradigm for patients with triple-negative breast cancer (TNBC) is set to undergo a dramatic transformation, as standard chemotherapeutic approaches are perfected and novel antibody-drug conjugates (ADCs) are developed. Kimberly Blackwell addressed this topic at the 2015 Chemotherapy Foundation Symposium, a meeting of over 1,000 oncologists and oncology professionals in New York City in November.

“I think we will see significant improvements in triple-negative breast cancer within the next few years,” said Blackwell, an oncologist at the Duke Cancer Institute. “There are two ADCs that I am fairly excited about that are in late stage development.”

Refining Chemotherapy for TNBC

In a phase 3 trial,¹ labeled Study 301, Halaven (eribulin mesylate) was compared with the chemotherapy capecitabine in previously treated patients with locally advanced or metastatic breast cancer. Patients were randomized to receive Halaven at 1.4 mg/m² on days 1 and 8 (554 patients) or capecitabine at 1250 mg/m² on days 1 to 14 (548patients).

Across the full population of the study, Halaven was not found to be superior to capecitabine for the coprimary endpoints of overall survival (OS) and progression-free survival (PFS). However, in a preplanned subgroup analysis of those with TNBC, a distinct advantage was seen.

“The one thing where this study actually changed my practice was this planned subgroup analysis of those women with triple-negative metastatic breast cancer,” Blackwell said. “This study validates that [intravenous] chemotherapy might be valuable in this population of first-line triple-negative breast cancer.”

In patients with TNBC (284 patients), there was a five-month improvement in OS with Halaven versus capecitabine. Median OS was 14.4 versus 9.4 months, for Halaven and capecitabine, respectively.

“When you see an overall survival advantage in the setting of women facing metastatic or incurable disease, you have to sit up and take note,” said Blackwell. "This study actually did shape my practice quite a bit, in terms of triple-negative breast cancer."

In a second phase 3 study,² labeled TNT, 376 patients with triple-negative or known BRCA1/2 mutation-positive metastatic breast cancer were treated with first-line chemotherapy (docetaxel or carboplatin). Patients were randomized to receive carboplatin at AUC 6 every three weeks (188 patients) or docetaxel at 100 mg/m² every three weeks (188 patients). Crossover was planned between the two arms following progression.

Across all patient groups, the objective response rate (ORR) with carboplatin was 31.4 percent compared with 35.6 percent for docetaxel. Following crossover similar findings were demonstrated.

“The only real difference in this study — that was very intriguing but validated some of the things were had been thinking — is that for those women facing breast cancer in the setting of a BRCA 1 or 2 mutations, the response rate was double, in favor of carboplatin over docetaxel,” Blackwell said.

In those with BRCA1/2-mutant breast cancer, ORR with carboplatin was 68.0 percent compared with 33.3 percent for docetaxel. In this same population, the median PFS with carboplatin was 6.8 versus 4.8 months with docetaxel. In the absence of BRCA1/2 mutations, the ORR with carboplatin was 28.1 percent versus 36.6 percent with docetaxel.

“This is the second randomized trial that basically changed my practice, in that it really demonstrated a role for platinums versus taxanes in women harboring a deleterious BRCA1/2 mutations,” Blackwell said.

Novel Strategies in TNBC

A number of novel therapies are on the horizon for treating TNBC, specifically those utilizing ADC technology. The two agents in this class generating the most excitement are glembatumumab vedotin (CDX-011) and sacituzumab govitecan (IMMU-132), explained Blackwell.

Glembatumumab vedotin comprised of the gpNMB-targeted human IgG2 monoclonal antibody CR011 linked with the tubulin polymerization inhibitor MMAE. In a phase 2 study for patients with metastatic TNBC,³ glembatumumab vedotin demonstrated exciting findings in the setting of metastatic TNBC, Blackwell noted.

The ORR in 16 patients with high expression of gpNMB was 33 percent with glembatumumab vedotin compared with 0 percent with investigator's choice of chemotherapy. When considering those with stable disease, the disease control rate with glembatumumab vedotin was 75 percent compared with 25 percent for those treated with chemotherapy.

Median PFS with the ADC was 3.5 versus 1.5 months with chemotherapy. Additionally, administration of the ADC nearly doubled OS compared with chemotherapy (median 10.0 vs 5.5 months).

The phase 2 METRIC study is currently exploring glembatumumab vedotin versus capecitabine in patients with gpNMB overexpressing TNBC who have received less than or equal to two prior therapies. The study will be randomized in a two-to-one ratio favoring the ADC, with PFS as the primary endpoint (NCT01997333).

The second ADC mentioned by Blackwell, sacituzumab govitecan, is a humanized IgG antibody targeted against Trop-2 conjugated to SN-38, which is an active metabolite of the chemotherapy irinotecan.

Sacituzumab govitecan was explored in a phase 1/2 study in heavily pretreated patients with TNBC who had received a median of four prior therapies (ranging from one to 11).⁴ Patients were not selected based on Trop-2, which is expressed in more than 80 percent of tumors.

In 56 evaluable patients, the ORR with sacituzumab govitecan was 30 percent, which included a complete response for two patients. The disease control rate with the ADC was 46 percent. The median PFS was seven months.

“Considering that these patients on average had received four lines of chemotherapy, these are pretty impressive results,” Blackwell said. “Many of us who are familiar with this data are excited about this compound moving forward.”

Androgen Receptor Signaling

The androgen receptor (AR) is frequently expressed on TNBC, suggesting that anti-androgen approaches could be successful. A phase 2 study examined this theory using the agent bicalutamide in metastatic AR-positive TNBC.⁵ At 24 weeks, the clinical benefit rate was 19 percent and the median PFS was 12 weeks.

Under the guise that Xtandi (enzalutamide) is eightfold more potent than bicalutamide, another phase 2 study was conducted looking at this second-generation anti-androgen agent in patients with TNBC with at least 1 percent AR expression.⁶ In evaluable patients (75 patients), the clinical benefit rate was 35 percent at 16 weeks and 29 percent by week 24. The ORR was 8 percent.

To further define a patient population most likely to response, a diagnostic test labeled PREDICT AR was developed based on the expression of 521 genes. Using this test, those who were positive experienced a significant extension in OS, when compared with the negative population. Based on these findings, studies have been launched in the United States and globally to further explore AR inhibition and the PREDICT AR test, Blackwell concluded.

References

1. Kaufman PA, Awada A, Twelve C, et al. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane [published online January 20, 2015]. J Clin Oncol. doi: 10.1200/JCO.2013.52.4892.
2. Tutt A, Ellis P, Kilburn L, et al. The TNT trial: A randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012). Presented at: San Antonio Breast Cancer Symposium. December 9-13, 2014; San Antonio, TX. Abstract S3-01.
3. Yardley DA, Weaver R, Melisko ME, et al. EMERGE: A randomized phase II study of the antibody-drug conjugate glembatumumab vedotin in advanced glycoprotein NMB—expressing breast cancer. J Clin Oncol. 2015;33(14):1609-1619.
4. Bardia A, Mayer I, Diamond J, et al. Safety and tumor responses of the anti-Trop-2 antibody drug conjugate, sacituzumab govitecan (IMMU-132), in refractory, metastatic, triple-negative breast cancer (TNBC): An ongoing Phase II trial. Presented at: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics, November 5-9, 2015. Abstract LB-C16.
5. Gucalp A, Tolaney S, Isakoff SJ, et al. Phase II trial of bicalutamide in patients with androgen receptor—positive, estrogen receptor–negative metastatic breast cancer. Clin Cancer Res. 2013;19(19): 5505—5512.
6. Traina TA, Miller K, Yardley DA, et al. Results from a phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC). J Clin Oncol. 2015;33 (suppl; abstr 1003).