Erin Roesch, MD
Metastatic triple-negative breast cancer (TNBC) is a heterogeneous, biologically complex subtype, with continuing efforts to identify therapeutic targets. The PI3K/AKT signaling pathway plays a key role in cell proliferation, survival, invasion, and metabolism. In the phase II LOTUS trial ( Dent et al ) including 124 patients with advanced TNBC (no prior therapy for advanced disease), addition of the oral AKT inhibitor, ipatasertib, to paclitaxel led to a numerical improvement in OS that was not statistically significant. The median OS was 25.8 vs 16.9 months for the ipatasertib-paclitaxel vs placebo-paclitaxel, respectively (HR 0.80, 95% CI 0.50-1.28). Findings from cohort A of the phase III IPATunity130 trial showed that ipatasertib-paclitaxel did not lead to a statistically significant improvement in PFS vs placebo-paclitaxel in patients with PIK3CA/AKT1/PTEN-altered advanced TNBC in the first-line metastatic setting (mPFS 7.4 vs 6.1 months, respectively; HR 1.02, p=0.9237). These findings support further investigation into predictors of response and other molecular markers that may play a role in the diversity of mTNBC.
Endocrine therapy resistance remains a significant challenge in advanced HR+/HER2- breast cancer, and initial studies with the oral histone deacetylase inhibitor, etinostat, showed promise in this space. Unfortunately, these findings were not upheld in the phase III E2112 trial ( Connolly et al ), which failed to show an improvement in PFS or OS with exemestane-etinostat (EE) compared to exemestane-placebo (EP) among patients who had progressed on prior non-steroidal AI. Median PFS was 3.3 vs 3.1 months (HR 0.87; p=0.30) and median OS was 23.4 vs 21.7 months (HR 0.99; p=0.94) for the EE vs EP arms, respectively. The combination of an alternative HDAC inhibitor, tucidinostat, has been approved in China in combination with exemestane based on PFS benefit (3.6 months) in the phase III ACE trial. There are notable difference between E2112 and ACE trials, including patient population and design, and importantly OS has not been reported for the latter. The relatively short mPFS and low response rate (5-6%) in E2112 argues for more efficacious therapeutics. There is also value in correlative studies to help further elucidate if there is a role for HDAC inhibitors in this space.
Although adjuvant endocrine therapy has had a significantly beneficial effect on outcomes in early-stage HR+ breast cancer, late recurrences are characteristic of the luminal subtype, and have led to trials investigating extended adjuvant endocrine therapy. The phase III SALSA trial included 3484 women with early HR+ breast cancer who had received 5 years of adjuvant endocrine therapy with randomization to anastrozole for an additional 2 vs 5 years (comparing total of 7 vs 10 years). There was no significant difference in disease-free survival (DFS) at 8 years (73.6% vs 73.9% in the 2 vs 5-year groups, respectively; HR 0.99, p=0.90). Additionally, there was a lower risk of bone fracture in the 2 vs 5-year group (4.7% vs 6.3%; HR 1.35). It is essential to balance modest benefits with toxicities of prolonged AI use, and valuable to identify high-risk patients who may benefit from extended adjuvant endocrine therapy.
References:
Chan A, Moy B, Mansi J, et al; ExteNET Study Group. Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial. Clin Breast Cancer. 2021;21(1):80-91.e7.
von Minckwitz G, Huang CS, Mano MS, et al; KATHERINE Investigators. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-628.
Dent R, Kim SB, Oliveira M, et al. Double-blind placebo-controlled randomized phase III trial evaluating first-line ipatasertib combined with paclitaxel for PIK3CA/AKT1/PTEN-altered locally advanced unresectable or metastatic triple-negative breast cancer: primary results from IPATunity130 cohort A. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Oral GS3-04.
Jiang Z, Li W, Hu X, et al. Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(6):806-815.
Mamounas EP, Bandos H, Lembersky BC, et al. Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NRG Oncology/NSABP B-42): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(1):88-99.