Current Treatment Landscape for Patients With Locally Recurrent Inoperable or Metastatic Triple-Negative Breast Cancer

A Systematic Literature Review

Claire H. Li; Vassiliki Karantza; Gursel Aktan; Mallika Lala

Disclosures

Breast Cancer Res. 2019;21(143) 

In This Article

Abstract and Introduction

Abstract

Background: Metastatic triple-negative breast cancer (mTNBC), an aggressive histological subtype, has poor prognosis. Chemotherapy remains standard of care for mTNBC, although no agent has been specifically approved for this breast cancer subtype. Instead, chemotherapies approved for metastatic breast cancer (MBC) are used for mTNBC (National Comprehensive Cancer Network Guidelines [NCCN] v1.2019). Atezolizumab in combination with nab-paclitaxel was recently approved for programmed death-ligand 1 (PD-L1)–positive locally advanced or metastatic TNBC. Published historical data were reviewed to characterize the efficacy of NCCN-recommended (v1.2016) agents as first-line (1L) and second-line or later (2L+) treatment for patients with locally recurrent inoperable or metastatic TNBC (collectively termed mTNBC herein).

Methods: A systematic literature review was performed, examining clinical efficacy of therapies for mTNBC based on NCCN v1.2016 guideline recommendations. Data from 13 studies, either published retrospective mTNBC subgroup analyses based on phase III trials in MBC or phase II trials in mTNBC, were included.

Results: A meta-analysis of mTNBC subgroups from three phase III trials in 1L MBC reported pooled objective response rate (ORR) of 23%, median overall survival (OS) of 17.5 months, and median progression-free survival (PFS) of 5.4 months with single-agent chemotherapy. In two subgroup analyses from a phase III study and a phase II trial (n = 40 each), median duration of response (DOR) to 1L chemotherapy for mTNBC was 4.4–6.6 months; therefore, responses were not durable. A meta-analysis of seven cohorts showed the pooled ORR for 2L+ chemotherapy was 11% (95% CI, 9–14%). Median DOR to 2L+ chemotherapy in mTNBC was also limited (4.2–5.9 months) per two subgroup analyses from a phase III study. No combination chemotherapy regimens recommended by NCCN v1.2016 for treatment of MBC showed superior OS to single agents.

Conclusions: Chemotherapies have limited effectiveness and are associated with unfavorable toxicity profiles, highlighting a considerable unmet medical need for improved therapeutic options in mTNBC. In addition to the recently approved combination of atezolizumab and nab-paclitaxel for PD-L1–positive mTNBC, new treatments resulting in durable clinical responses, prolonged survival, and manageable safety profile would greatly benefit patients with mTNBC.

Introduction

Breast cancer (BC) is the most common malignant neoplasm in females; an estimated 266,120 new diagnoses and 40,920 related deaths occurred in the USA in 2018.[1] Approximately 10–20% of BCs do not express estrogen and progesterone receptors and lack amplification/overexpression of the human epidermal growth factor 2 receptor (HER2);[2–4] therefore, they are known as triple-negative breast cancers (TNBCs) and constitute an aggressive histologic subtype. In patients with locally recurrent inoperable or metastatic disease (collectively referred to as mTNBC in this article), treatment options have primarily been chemotherapies based on recommended therapeutic approaches (National Comprehensive Cancer Network [NCCN] v1.2019 guidelines and the European School of Oncology-European Society for Medical Oncology [ESO-ESMO] 2018 guidelines) for metastatic breast cancer (MBC).[5,6] In particular, anthracyclines, taxanes, capecitabine, and more recently, eribulin are commonly used as monotherapy or in combination with other agents and as standard/control arms in registration trials of new/investigational agents for TNBC. Anthracyclines and taxanes are both recommended, unless contraindicated, as first-line (1L) treatments for patients who have not previously received these agents as neoadjuvant or adjuvant treatment.[5,6] The efficacy of anthracyclines in mTNBC has been inferred from earlier studies that involved patients with MBC in which the TNBC subpopulation was not distinctly defined (mostly because of the absence of HER2 status reporting).[7] Compared with taxanes, anthracyclines have not demonstrated overall survival (OS) benefit in mTNBC.[8] Because data on the effectiveness of anthracyclines are not available in the mTNBC population and anthracyclines and taxanes are generally considered similarly effective, anthracyclines are not discussed further in this review.

Overall prognosis for patients with mTNBC is worse than for the other BC subtypes, and more effective therapeutic options are needed. In a pooled analysis of two phase III trials in MBC, inferior outcomes were reported with 1L or later line physician choice of chemotherapy for patients with mTNBC than for the overall MBC population.[9] Chemotherapies are generally associated with unfavorable adverse events (AEs), more so in combination, that can lead to treatment discontinuation. Because combination regimens have not prolonged OS compared with monotherapies, the approach recommended by the NCCN v1.2019/ESO-ESMO 2018 guidelines[5,6] for the treatment of MBC (including mTNBC) remains sequential use of single-agent chemotherapy. Based on recent evidence that atezolizumab plus nab-paclitaxel improves progression-free survival (PFS), this combination was recently granted accelerated approval by the US Food and Drug Administration (FDA) in patients with programmed death-ligand 1 (PD-L1)–positive (immune cell score, IC 1+) TNBC.[5,10,11] In general, clinical trials conducted only in patients with mTNBC are limited. No phase III trials have been conducted to specifically evaluate single agents as treatment for mTNBC in any line of therapy, and only a limited number of phase III trials have been conducted to evaluate combination therapies in the mTNBC population. The purpose of the current evidence synthesis was to systematically characterize the efficacy of commonly used chemotherapies, defined herein to be agents recommended in the NCCN v1.2016 guidelines (which were current at the time of this analysis),[12] as 1L and second-line or later (2L+) treatment for patients with mTNBC, thereby providing a summary of available historical data.

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