Carey Offers Views on Evolving Chemotherapy Options-and Beyond-in TNBC

Lisa Carey, MD

Treating patients with triple-negative breast cancer (TNBC) remains a challenge because these tumors do not rely on hormone receptors or HER2 amplification for tumor growth. TNBC is a heterogeneous disease that is not defined by a specific biology; therefore, the standard of care remains cytotoxic chemotherapy rather than targeted therapy. A single chemotherapeutic agent is commonly used, with combination chemotherapy reserved for those patients with TNBC who have particularly symptomatic or rapidly progressing visceral disease.

Lisa A. Carey, MD, professor at the University of North Carolina (UNC) Chapel Hill and researcher at the UNC Breast Center, discussed the management of TNBC at the Miami Breast Cancer Conference. OncLive spoke with Carey about recent developments for patients with triple-negative disease.

“What’s new in chemotherapy treatment options is results from a study called the Triple Negative Breast Cancer Trial or TNT reported this past December at the San Antonio Breast Cancer Symposium [SABCS],” said Carey. “This study is the first hint that we could, and should, make different choices of chemotherapy regimens based on the type of triple-negative breast cancer.”

The United Kingdom-based, randomized, head-to-head TNT1 investigated whether patients with previously untreated metastatic TNBC respond better to a taxane, the current standard of care, or a platinum-based chemotherapy regimen. Prior to the study, data on whether or not certain patients with TNBC respond better to a platinum-based chemotherapy were lacking.

The phase III trial randomized 376 patients with TNBC to six cycles every 3 weeks of either carboplatin at the full AUC6 dose or the standard of care first-line therapy of docetaxel, 100 mg/m².

“Typically, platinum-based chemotherapies are used later in treatment, but the TNT study showed that either docetaxel or carboplatin worked well as first-line therapy, which is helpful for those of us treating patients, as it provides more options in the front-line setting,” said Carey. Neither the response rate nor progression-free survival (PFS) or overall survival (OS) was different between the two treatment arms. A prespecified subset analysis showed that patients with a germline BRCA1 or BRCA2 mutation had a higher proportion of objective responses and greater PFS when treated with carboplatin compared with docetaxel. The median PFS for patients with BRCA1/2 mutations was 6.8 months in the carboplatin arm compared with 4.8 months in the docetaxel arm. Prior small studies had hinted that BRCA-mutated tumors may respond better to platinum-based chemotherapy, but this is the first trial to formally address this question, according to Carey.

Additionally, non—basal-like tumors appeared to have a higher response to docetaxel compared with carboplatin, but the number of patients with basal-like tumors was too small to draw conclusions, Carey noted.

“Based on this study, carboplatin is now on my list of first-line options for sporadic triple-negative breast cancer,” said Carey. “I generally chose between a taxane and platinum chemotherapy based on toxicities. Platinum chemotherapies result in less neuropathy compared to taxanes, but platinum-based regimens are also accompanied by more nausea and myelosuppression and can be harder on the kidneys compared to taxanes. Platinum-based chemotherapy is not a low-toxicity regimen, but rather, has different toxicities and may be more suitable for some patients.” In TNT, the docetaxel arm had a higher frequency of febrile neutropenia and neuropathy compared with the carboplatin arm (P <.01).

Beyond Chemotherapy

A type of immunotherapy known as checkpoint inhibition has proven effective in melanoma, renal cell carcinoma, and lung cancer. While not historically an immune-responsive cancer type, a recent phase I trial,² also reported at the 2014 SABCS, showed that the anti-programmed cell death protein-1 (PD-1) antibody, pembrolizumab, has activity in TNBC. Pembrolizumab was recently approved for treatment of metastatic melanoma. The phase Ib TNBC study is the first to show responses to a PD-1 antibody in breast cancer.

The study recruited 32 women with PD-L1—positive, recurrent, metastatic TNBC. Patients were treated with 10 mg/kg pembrolizumab every 2 weeks until progression or unacceptable toxicity. Patients on the trial had a median age of 51.9 years, and most patients had received and progressed on at least two lines of chemotherapy for metastatic disease.

Among the 27 patients who could be evaluated for response, 18.5% had an objective response including one complete response (3.7%) and four partial responses (14.8%). Seven patients (25.9%) had stable disease. The median time to response was 9.9 months. Three of the five responders have been on treatment for at least 11 months.

Five patients (15.6%) had at least one drug-related serious adverse event (AE). One of these AEs, disseminated intravascular coagulation (DIC) with thrombocytopenia and decreased blood fibrinogen, resulted in death. The safety profile was acceptable in this relatively heavily pretreated cohort, the study authors concluded.

“While the study is small, the responses seen were really durable,” said Carey. A phase II study of pembrolizumab in TNBC is being planned to start in 2015.

Another immune checkpoint inhibitor, MPDL3280A, an anti— PD-L1 antibody, against the ligand of PD-1, is also being investigated for TNBC as part of a phase I solid tumor clinical trial.³ Early phase I data on patients with TNBC were also reported at the 2014 SABCS.⁴ Of nine patients with PD-L1—positive tumors evaluated thus far, three responded, including one complete response. The trial is still recruiting patients with both PD-L1– positive and PD-L1–negative TNBC and other tumor types.

TNBC Subclasses

“There are lots of [sequencing] data already on subclasses within TNBC, and there will be more of those kinds of studies,” said Carey. “How that is going to help treat patients is still an unwritten chapter.”

Many TNBC primary tumors have been sequenced, but sequencing of primary tumors thus far has not been helpful because these tumors have few actionable mutations. New efforts are focusing on sequencing metastatic TNBC tumors. In estrogen-receptor—positive tumors, sequencing metastatic tumors may be relevant to treatment as new, clinically relevant mutations not seen in the primary tumor have been identified post treatment, according to Carey. “Whether that is true in triple-negative breast cancer remains to be seen.”

According to Carey, DNA sequencing of tumors may be less helpful compared with RNA expression levels, epigenetics, and protein levels. The Breast Cancer Research Fund is funding the AURORA US and AURORA EU studies to evaluate metastatic breast cancer samples to better understand the molecular biology of metastatic tumors and to develop clinical trials based on these findings. Academic centers including UNC Lineberger Comprehensive Cancer Center are collaborating to analyze metastatic tumors retrospectively and then conduct prospective studies focused on metastatic TNBC tissue. The goals are to identify metastatic-specific molecular and genetic markers of breast cancer and to track these changes in individual patients over time as a response to treatment.

References

1. 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). San Antonio Breast Cancer Symposium 2014. Dec. 9-13, 2014; San Antonio, TX. Abstract S3-01.
2. Nanda, R, Chow LQ, Dees EC, et al. A phase Ib study of pembrolizumab (MK-3475) in patients with advanced triple-negative breast cancer. San Antonio Breast Cancer Symposium 2014. Dec. 9-13, 2014; San Antonio, TX. Abstract S1-09.
3. ClinicalTrials.gov. A phase 1 study of MPDL3280A (an Engineered Anti-PDL1 antibody) in patients with locally advanced or metastatic solid tumors, NCT01375842
4. Emens LA, Braiteh FS, Cassier P, et al. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer. Presented at 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, Texas. Abstract PD1-6.