Promising Agents Could Alter the Treatment Paradigm in Metastatic TNBC

Jason Harris
Published: Monday, Oct 15, 2018
Joyce A. O’Shaughnessy, MD

Joyce A. O’Shaughnessy, MD

Since triple-negative breast cancer (TNBC) is resistant to multiple therapies, physicians have little flexibility for treatment options. However, anticipation is building for potential alternatives. “Right now, for TNBC, chemotherapy is our only option,” said Joyce A. O’Shaughnessy, MD, co-chair of Breast Cancer Research and the chair of Breast Cancer Prevention Research at Baylor- Sammons Cancer Center in Dallas, Texas. “That’s about to change very soon with the likely availability of atezolizumab [Tecentriq].”

Further, research into novel therapies for metastatic BRCA-mutated TNBC, including PI3K/ AKT/mTOR pathway inhibitors and antibody–drug conjugates (ADCs), could soon result in a host of new therapies for this hard-to-treat disease.

Standard-of-care doxorubicin (Adriamycin) and cyclophosphamide followed by paclitaxel (Taxol; AC/T) chemotherapy induces a 5-year disease-free survival of 65% to 80% and a pathological complete response (pCR) rate of 30% to 42% in patients with TNBC. The pCR rate rises to 54% to 58% with the addition of carboplatin to AT chemotherapy. pCR is associated with excellent outcomes, but the recurrence rate for patients who do not achieve a pCR is 30% to 70%. For metastatic disease, the overall survival (OS) is 12 to 18 months. Treatment consists of sequential single-agent chemotherapy. The only clinically available targeted agents target germline BRCA carriers.

Genetech, the manufacturer of atezolizumab, in July announced topline results from the phase III IMpassion130 trial showing that the anti–PD-L1 monoclonal antibody combination with nab-paclitaxel (Abraxane) demonstrated statistically significant improvement in progression-free survival (PFS) in treatment-naïve patients with locally advanced or metastatic TNBC.

The company also reported encouraging OS findings in the PD-L1–positive population. Furthermore, no new safety signals emerged with the combination, and adverse events were consistent with previous single-agent use of the drugs. Investigators are also exploring atezolizumab in combination with paclitaxel for patients with inoperable locally advanced or metastatic TNBC in the ongoing phase III IMpassion131 (NCT03125902). PFS is the primary endpoint of the study.

Atezolizumab/nab-paclitaxel is a promising treatment for patients with TNBC, but it is hardly the only therapy under investigation. In a presentation in July during the 17th Annual International Congress on the Future of Breast Cancer® East, held by Physicians’ Education Resource® in New York, O’Shaughnessy walked her audience through the most recent findings and ongoing research in the field, focusing on agents inhibiting the PI3K/AKT signaling pathway and the ADC sacituzumab govitecan.


The PI3K/AKT/mTOR signaling pathway is frequently activated in TNBC. Furthermore, deficient PTEN expression is often found in TNBC and is associated with a higher degree of PI3K pathway activation.

First-line PI3K/AKT inhibition has shown promising activity in combination with pacl- itaxel in a pair of phase II placebo-controlled trials, LOTUS and PAKT, and in a phase I/II trial exploring alpelisib (BYL719) plus nab-paclitaxel in patients with locally recurrent or metastatic HER2-negative breast cancer (TABLE).1-6

“This is an important emerging story,” O’Shaughnessy said. “[These trials] are beginning to enrich for the TNBCs in the metastatic setting that have genomic alterations in the PI3 kinase pathway. AKT is a very important nodal point in TNBC.” The LOTUS trial included 126 patients who were chemotherapy-free for at least 6 months and who had not received systemic treatment for advanced or metastatic disease. Sixty-two patients were assigned to 400 mg of daily ipatasertib, an oral AKT inhibitor, on days 1 to 21 of a 28-day cycle. Another 62 patients were assigned to placebo. Both groups received 80 mg/m2 of paclitaxel on days 1, 8, and 15 of a 28-day cycle.2

The median PFS in the intent-to-treat (ITT) population (n = 124) was 6.2 months in the ipatasertib arm versus 4.9 months in the placebo arm (stratified HR, 0.60; 95% CI, 0.37-0.98; P = .037).

The median PFS benefit among the 42 patients with PIK3CA/AKT1/PTEN-altered tumors was stronger (9.0 vs. 4.9 months; unstratified HR, 0.44; 95% CI, 0.20-0.99; log-rank P = .041).

Interim survival data presented in June at the 2018 American Society of Clinical Oncology Annual Meeting from the ITT population showed a median OS of 23.1 months in the ipatasertib arm, compared with 18.4 months with placebo (stratified HR, 0.62; 95% CI, 0.37-1.05).3

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