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Dramatic Changes Underway in TNBC Treatment Landscape

Silas Inman @silasinman
Published: Wednesday, Nov 25, 2015

Dr. Kimberly L. Blackwell

Kimberly L. Blackwell, MD

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, according to Kimberly Blackwell, MD, at the 2015 Chemotherapy Foundation Symposium.

“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 III trial,1 labeled Study 301, eribulin mesylate was compared with capecitabine in previously treated patients with locally advanced or metastatic breast cancer. Patients were randomized to receive eribulin at 1.4 mg/m2 on days 1 and 8 (n = 554) or capecitabine at 1250 mg/m2 on days 1 to 14 (n = 548).

Across the full population of the study, eribulin 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 IV chemotherapy might be valuable in this population of first-line triple-negative breast cancer.”

In patients with TNBC (n = 284), there was a 5-month improvement in OS with eribulin versus capecitabine. Median OS was 14.4 versus 9.4 months, for eribulin and capecitabine, respectively (HR, 0.702; 95% CI, 0.545-0.906).

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

Across all patient groups, the objective response rate (ORR) with carboplatin was 31.4% compared with 35.6% for docetaxel (P = .44). 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% compared with 33.3% for docetaxel (P = .03). 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% versus 36.6% with docetaxel (P = .16).

“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 II 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% with glembatumumab vedotin compared with 0% with investigator's choice of chemotherapy. When considering those with stable disease, the disease control rate with glembatumumab vedotin was 75% compared with 25% for those treated with chemotherapy.

Median PFS with the ADC was 3.5 versus 1.5 months with chemotherapy (HR, 0.11). Additionally, administration of the ADC nearly doubled OS compared with chemotherapy (median 10.0 vs 5.5 months; HR, 0.14).

The phase II METRIC study is currently exploring glembatumumab vedotin versus capecitabine in patients with gpNMB overexpressing TNBC who have received ≤2 prior therapies. The study will be randomized in a 2:1 ratio favoring the ADC, with PFS as the primary endpoint (NCT01997333).

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