Novel Therapeutic Strategies for Metastatic TNBC

Joyce O’Shaughnessy, MD,

An evolving understanding of the biology and heterogeneity of triple-negative breast cancer (TNBC) is helping to refine existing approaches to treating patients and is yielding intriguing insights into current and novel therapies, according to Joyce A. O’Shaughnessy, MD.

O’Shaughnessy provided an analysis of emerging therapeutic strategies for TNBC during a presentation at the 16th Annual International Congress on the Future of Breast Cancer^® West that Physicians’ Education Resource (PER^®) hosted July 14-15 in San Diego, California. She is the co-chair of Breast Cancer Research and chair of Breast Cancer Prevention Research at Baylor-Sammons Cancer Center in Dallas and for The US Oncology Network and she served as program co-chair for the conference.

Molecular Subtyping

In her presentation, O’Shaughnessy covered a broad range of data concerning multiple new and approved drugs. Here are some of the key areas she discussed:So far, the clinical utility of molecular subtyping approaches in TBNC has not been established but it is shaping up to be valuable knowledge, with some therapeutic signals that correlate with subtypes, O’Shaughnessy said.

There have been several studies delineating intrinsic subtypes in TNBC, O’Shaughnessy said, notably a 2016 analysis that refined TNBC molecular subtypes into 4 tumor-specific categories: basal-like 1, basal-like 2, mesenchymal, and luminal androgen receptor.¹ Lehmann et al retrospectively examined pretreatment tissue samples from 300 patients with TNBC and found significant differences among the subtypes in pathological complete responses to neoadjuvant chemotherapy.

Chemotherapy Doublets

“This subtyping is more to help us as clinicians begin to think about what to do with this very heterogeneous disease and why clinical trials are evolving as they are,” said O’Shaughnessy.Although research findings have not been specifically matched with a molecular subtype in the tnAcity study, O’Shaughnessy pointed to the results of the phase II trial as setting the stage for a new first-line chemotherapy doublet for patients with TNBC.

In the study, 191 patients were randomized to receive nab-paclitaxel (Abraxane) plus carboplatin (n = 64), nab-paclitaxel plus gemcitabine (n = 61), or gemcitabine plus carboplatin (n = 66. The overall response rate (ORR) was 72% with the nab-paclitaxel/carboplatin regimen compared with 39% and 44%, respectively, for the gemcitabine-containing regimens.²

The combination of nab-paclitaxel plus carboplatin proved superior in median progression-free survival (PFS): 7.4 months compared with 5.4 months for nab-paclitaxel/gemcitabine (HR, 0.60; CI 95%, 0.39-0.93; P = .02) and 6.0 months for gemcitabine/carboplatin (HR, 0.61; 95% CI, 0.39-0.94; P = .03). The median overall survival was 16.4 months with nab-paclitaxel/carboplatin versus 12.1 months with nab-paclitaxel plus gemcitabine (HR, 0.66; CI 95%, 0.42-1.04; P = .07) and 12.6 months with gemcitabine plus carboplatin HR, 0.74; CI 95%, 0.48-1.16; P = .17).

Regarding the toxicity profile, O’Shaughnessy noted that the nab-paclitaxel regimens were more favorable from a myelosuppression standpoint.

PARP Inhibitors

O’Shaughnessy said gemcitabine plus carboplatin has been historically used as the doublet of choice for this patient population. However, based on the tnAcity findings, “it would not be unreasonable to consider a nab-paclitaxel and carboplatin combination as an option,” she said.The strategy of using a PARP inhibitor to target the DNA repair mechanism proved effective in the phase III OlympiAD study in which olaparib (Lynparza) provided a statistically significant PFS benefit for patients with TNBC. ³ The safety profile of olaparib was consistent with prior studies.

In this study, 302 patients were randomized, with 205 patients receiving olaparib and 91 receiving the single-agent chemotherapy of physician’s choice, such as capecitabine (Xeloda), eribulin (Halaven), or vinorelbine (Navelbine). Patients on the olarparib arm received 300 mg twice a day until objective disease progression or unmanageable toxicity. PFS was the primary endpoint.

The study enrolled patients with HER2-negative metastatic breast cancer including participants with estrogen receptor— and/or progesterone receptor–positive disease or TNBC. Patients were required to have a germline mutation in BRCA1/2 genes, which are important components of a key DNA repair pathway.

Overall, the results showed that patients who received olaparib achieved a median PFS of 7.0 months compared with 4.2 months for those who received chemotherapy (HR, 0.58; 95% CI, 0.43-0.80; P = .0009). The ORR also was higher with olaparib at 60% versus 29% with chemotherapy; however, the durability of the response was similar at 6.2 versus 7.1 months, respectively. Among patients with TNBC, the rate of progression or death was 79.4% with olaparib compared with 83.3% with chemotherapy (HR, 0.42; 95% CI, 0.29-0.63).

Adverse events (AEs) grade 3 or higher appeared in 36.6% and 50.5% in the olaparib and chemotherapy arms, respectively, demonstrating an improved quality of life. There was no significant difference in OS, although data were not fully mature.

According to O’Shaughnessy, this was a positive and significant trial for patients in a germline BRCA-mutation population that was heavily pretreated. “We hope that this will become FDA approved and that this will be our first PARP inhibitor option,” she said.

PI3K/AKT Pathway

She noted that an important phase III trial evaluating olaparib in the adjuvant setting is ongoing. The OlympiA study is seeking to enroll 1500 patients with germline BRCA1/2 mutations and high-risk HER2-negative breast cancer who have completed definitive local treatment and neoadjuvant or adjuvant chemotherapy (NCT02032823).The PI3K/AKT pathway has long been recognized as an active signaling network in the development of breast cancer, O’Shaughnessy said. Ipatasertib, an oral AKT inhibitor, has demonstrated positive results in combination with paclitaxel as first-line therapy for TNBC in the phase II LOTUS trial.

In recently published clinical trial results, the ipatasertib combination resulted in a median PFS in the intention-to-treat population of 6.2 months versus 4.9 months in the paclitaxel-alone arm (HR, 0.60; 95% CI, 0.37-0.98; P = .037).⁴

The benefit was more pronounced among participants whose tumors harbored mutations in PIK3CA, AKT1, or PTEN. Patients with alterations who received ipatasertib (n = 26) achieved a median PFS of 9.0 months compared with 4.9 months for those with mutated tumors who received paclitaxel alone (HR, 0.44; 95% CI, 0.20-0.99).

Eribulin Update

O’Shaughnessy said she expects ipatasertib to be explored in genomically selected populations in combination with paclitaxel or another partner. She noted that there are many questions to be answered but that the drug “could really be quite exciting.”Eribulin (Halaven), a cytotoxic microtubule inhibitor, was approved in the United States in 2010 for the treatment of metastatic breast cancer after at least 2 treatment regimens including an anthracycline and a taxane. This was due to the results of the EMBRACE trial, which compared eribulin with physician’s choice of standard chemotherapies in patients with locally recurrent or metastatic breast cancer.⁵

A recent trial, Study 301, compared eribulin with capecitabine in patients with metastatic breast cancer refractory to recent chemotherapy. The findings did not show a statistically significant benefit in favor of eribulin for the overall study (N = 1102).⁶ However, a subgroup analysis demonstrated a trend toward improved OS among patients with TNBC: 12.9 months among those who received eribulin versus 8.2 months with capecitabine (P = .006).

In recent preclinical studies of human breast cancer models, eribulin was shown to alter the tumor microenvironment. The agent causes vascular remodeling, which restores oxygen flow to hypoxic regions within the tumor. Hypoxia has been associated with phenotypical changes that lead to metastasis. Additionally, in these breast cancer models, eribulin also effectively stopped the metastatic mesenchymal phenotype while promoting epithelial cells.

O’Shaughnessy discussed the potential of the combination of eribulin and pembrolizumab (Keytruda), a PD-1 inhibitor. Findings from a phase Ib/II study demonstrated an ORR of 33.3% for patients with metastatic TNBC (N = 39) who had received 0 to 2 prior lines of chemotherapy. The safety profile of the combination was similar to the safety profiles of the agents individually, with the most common toxicities being fatigue seen in 74.4% of patients, nausea in 51.3%, and peripheral neuropathy in 43.6%. O’Shaughnessy noted that this looks like an interesting combination for further pursuit.

“Some of our older agents might be able to reverse to epithelial biology and might make the checkpoint inhibitors work better,” said O’Shaughnessy.

References

1. Lehmann BD, Jovanovic B, Chen X, et al. Refinement of triple-negative breast cancer molecular subtypes: implications for neoadjuvant chemotherapy selection. PLoS One. 2016;11(6): e0157368. doi: 10.1371/journal.pone.0157368.
2. Yardley D, Coleman R, Conte P, et al. Nab-paclitaxel + carboplatin or gemcitabine vs gemcitabine/carboplatin as first-line treatment for patients with triple-negative metastatic breast cancer: results from the randomized phase 2 portion of the tnAcity trial. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Poster P5-15-03. sabcs16.posterview.com/nosl/i/P5-15-03.
3. Robson ME, Im S, Senkus E, et al. OlympiAD: Phase III trial of olaparib monotherapy versus chemotherapy for patients with HER2-negative metastatic breast cancer (mBC) and a germline BRCA mutation (gBRCAm). J Clin Oncol. 2017;35(suppl; abstr 1009). http://abstracts.asco.org/199/AbstView_199_186720.html.
4. Kim SB, Dent R, IM SA, et al; the LOTUS Investigators. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial [published online August 8, 2017]. Lancet Oncol. doi: 10.1016/S1470-2045(17)30450-3
5. Twelves C, Loesch D, Blum JL, et al. A phase III study (EMBRACE) of eribulin mesylate versus treatment of physician’s choice in patients with locally recurrent or metastatic breast cancer previously treated with an anthracycline and a taxane [ASCO abstract CRA1004]. J Clin Oncol. 2010;28(suppl 18). doi: 10.1200/jco.2010.28.18_suppl.cra1004.
6. Kaufman PA, Awada A, Twelves 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. J Clin Oncol. 2015;33(6):594-601. doi: 10.1200/JCO.2013.52.4892.
7. Tolaney S, Savulsky C, Aktan G, et al. Phase 1b/2 study to evaluate eribulin mesylate in combination with pembrolizumab in patients with metastatic triple-negative breast cancer. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract P5-15-02. sabcs16.posterview.com/nosl/i/P5-15-02.