Current treatment landscape for patients with locally recurrent inoperable or metastatic triple-negative breast cancer: a systematic literature review

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.

Keywords: Chemotherapy; Immune checkpoint inhibitor; Metastatic triple-negative breast cancer; PARP inhibitor.

Fig. 1

Study selection process for the systematic literature review and meta-analysis of breast cancer (BC). *Exclusions include not phase II, not phase III or phase II with triple-negative breast cancer (TNBC) focus, phase II not TNBC focus, not phase II or phase III, and not TNBC focus phase II/I. ^†Exclusions include review articles, other study types, not recurrent/metastatic (R/M) of phase III/II data, and not TNBC-specific R/M. ^‡Exclusions include non-cancer outcomes focus, only quality-of-life data, study protocol, surgical intervention, model development, and only AE data. ^§Exclusions include other language, older report of the same study, and reference unavailable. ^‖Results from one study (phase III trial, study 301) based on internal communication with sponsor (Eisai); not published results. ^¶Results from Twelves et al.’s [9] and Pivot et al.’s [13] studies are both included based on the reported different treatment line outcomes

Fig. 2

Historical objective response rate (ORR) with chemotherapy in 2L+ mTNBC. Meta-analysis of the seven cohorts from six studies reporting ORR with single-agent chemotherapy in second or later line treatment settings

Fig. 3

Graphical representations of objective response rates (ORRs) for a trials of NCCN-recommended (v1.2016) second-line (2L) plus monotherapy (including studies mixed with first-line [1L]), and b trials of NCCN-recommended (v1.2016) first-line monotherapy; the size of the bubble is proportional to the study size (all-patients-as-treated population), and the color of the bubble indicates the line of therapy. Yellow = 1L, green = 2L–3L+, pink = 2L, blue = 1L–3L+ (including studies with ≤ 15% 1L patients). Study 301 result is based on internal communication with trial sponsor (Eisai); not published results

Fig. 4

Graphical representation of overall survival (OS) for a trials of NCCN-recommended (v1.2016) second-line (2L) plus monotherapy (including studies mixed with first-line [1L]), and b trials of NCCN-recommended (v1.2016) 1L monotherapy; the size of the bubble is proportional to the study size (all-patients-as-treated population), and the color of the bubble indicates the line of therapy. Yellow = 1L, green = 2L–3L+, pink = 2L, blue = 1L–3L+ (including studies with ≤ 15% 1L patients). Study 301 result is based on internal communication with trial sponsor (Eisai); not published results. OS from phase II 2015 study is based on a total of 86 patients, including 80% 1L and 20% 2L+ patients