O'Shaughnessy Shares Novel Therapeutic Strategies for Treating Metastatic TNBC

Joyce O'Shaughnessy, MD

With an explosion of novel agents on the horizon for patients with metastatic triple-negative breast cancer, the treatment paradigm continues to evolve. Joyce O’Shaughnessy, MD, recently provided an update on existing research and a look at the future.

At the PER^®Future of Breast Cancer^®West conference in San Diego, California, O’Shaughnessy, 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 discussed the novel therapeutic strategies for metastatic TNBC.

Chemotherapy Doublets

In the phase II tnAcity study, frontline nab-paclitaxel (Abraxane) plus carboplatin lowered the risk of disease progression or death by 40% compared to 2 other chemotherapy regimens in patients with metastatic TNBC.

According to O’Shaugnessy, gemcitabine (Gemzar) plus carboplatin has been historically used as the doublet of choice in those patients. However, this study demonstrated the highest response rate of 92% with nab-paclitaxel versus 40% with other doublets.¹

In regards to the toxicity profile, O’Shaugnessy states that from a myelosuppression standpoint, nab-paclitaxel was more favorable. There was a statistically significant improvement in progression-free survival (PFS) with the nab-paclitaxel arm, demonstrating 7.4 months whereas the gemcitabine combination arm had a PFS of 6 months.¹

“It would not be unreasonable to consider a nab-paclitaxel and carboplatin combination as an option,” said O’Shaughnessy.

Olaparib

Based on the phase III OlympiAD study, olaparib (Lynparza) provided a statistically significant PFS benefit to patients with HER2-negative metastatic breast cancer, estrogen receptor-positive and/or progesterone receptor-positive breast cancer, or TNBC. 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.²

The primary endpoint was PFS with secondary endpoints including time to second progression or death, overall survival (OS), and objective response rate (ORR). 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 difference in OS.²

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

Ipatasertib

Ipatasertib, an oral AKT inhibitor, is currently being investigated in cancers with a high prevalence of PI3K/Akt pathways, including TNBC. The Lotus trial investigated ipatasertib combined with paclitaxel and discovered it modestly improved PFS for patients with measurable, inoperable, locally advanced/metastatic TNBC previously untreated with systemic therapy. Treatment continued until disease progression, intolerable toxicity, or withdrawal of consent.³

The primary endpoint was PFS with the secondary endpoints including ORR, OS, and duration of response. The most common AEs included diarrhea, peripheral neuropathy, and pneumonia. The effects of treatment were more pronounced in patients withPI3KCA/AKT1/PTENalterations.

Eribulin

According to O’Shaughnessy, there are many questions that still need to be answered in this space, but the phase III Lotus data will be eagerly anticipated.

Eribulin, an anti-invasive antigen, 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 to physician’s choice of standard chemotherapies in patients with locally recurrent or metastatic breast cancer.⁴

The more recent study, Study 301, compared eribulin with capecitabine in patients with metastatic breast cancer refractory to recent chemotherapy. This study showed no statistically significant difference between the 2 treatments; however, eribulin demonstrated a trend toward improved OS.⁵

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 pembrolizumab and eribulin, which was investigated in a phase Ib/II study which demonstrated an objective response rate of 33.3% for patients with metastatic TNBC who received 0 to 2 prior lines of therapy. 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 quite an interesting combination for further pursuit.⁶

References:

1. 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. Abstract P5-15-03.
2. 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.
3. Dent RE, Kim S, Im S, et al. Lotus (NCT02162719): A double-blind placebo (PBO)-controlled randomized phase II trial of first-line ipatasertib (IPAT) + paclitaxel (P) for metastatic triple-negative breast cancer (TNBC).J Clin Oncol.2017;35(suppl; abstr 1009). http://abstracts.asco.org/199/AbstView_199_183382.html.
4. 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.J Clin Oncol.suppl.cra1004. doi:10.1200/jco.2010.28.18.
5. 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). doi: 10.1200/JCO.2013.42.4892.
6. 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.