Efficacy and Safety of Weekly Paclitaxel With or Without Oral Alisertib in Patients With Metastatic Breast Cancer

Abstract

IMPORTANCE Elevated expression of AURKA adversely affects prognosis in estrogen receptor (ER)-positive and ERBB2 (formerly HER2)-negative and triple-negative breast cancer and is associated with resistance to taxanes. OBJECTIVE To compare paclitaxel alone vs paclitaxel plus alisertib in patients with ER-positive and ERBB2-negative or triple-negative metastatic breast cancer (MBC). DESIGN, SETTING, AND PARTICIPANTSIn this randomized clinical trial conducted with the US Oncology Network, participants were randomized to intravenous (IV) paclitaxel 90 mg/m 2 on days 1, 8, and 15 on a 28-day cycle or IV paclitaxel 60 mg/m 2 on days 1, 8, and 15 plus oral alisertib 40 mg twice daily on days 1 to 3, 8 to 10, and 15 to 17 on a 28-day cycle. Stratification was by prior neo or adjuvant taxane and by line of metastatic therapy. Eligible patients were those who had undergone endocrine therapy, 0 or 1 prior chemotherapy regimens for MBC, more than 12 months treatmentfree interval from neo or adjuvant taxane therapy, and with measurable or evaluable lytic bonedisease. Data were analyzed from March 2019 through May 2019. MAIN OUTCOMES AND MEASURES The main outcome was progression-free survival (PFS) with secondary end points of overall survival (OS), overall response rate, clinical benefit rate, safety, and analysis of archival breast cancer tissues for molecular markers associated with benefit from alisertib. RESULTS A total of 174 patients were randomized, including with 86 randomized to paclitaxel and 88 patients randomized to paclitaxel plus alisertib, and 169 patients received study treatment. The final cohort included 139 patients with a median (interquartile range [IQR]) age of 62 (27-84) years with ER-positive and ERBB2-negative MBC, with 70 randomized to paclitaxel and 69 randomized to paclitaxel plus alisertib. The TNBC cohort closed with only 35 patients enrolled due to slow accrual and were not included in efficacy analyses. The median (IQR) follow-up was 22 (10.6-25.1) months, and median (IQR) PFS was 10.2 (3.8-15.7) months with paclitaxel plus alisertib vs 7.1 (3.8-10.6) monthswith paclitaxel alone (HR, 0.56; 95% CI, 0.37-0.84; P = .005). Median (IQR) OS was 26.3 (12.4-37.2) months for patients who received paclitaxel plus alisertib vs 25.1 (11.0-31.4) months for paclitaxel alone (HR, 0.89; 95% CI, 0.58-1.38; P = .61). Grade 3 or 4 adverse events occurred in 56 patients (84.8%) receiving paclitaxel plus alisertib vs 34 patients (48.6%) receiving paclitaxel alone. The main grade 3 or 4 adverse events with paclitaxel plus alisertib vs paclitaxel alone were neutropenia (50 patients [59.5%] vs 14 patients [16.4%]), anemia (8 patients [9.5%] vs 1 patient [1.2%]), diarrhea (9 patients [10.7%] vs 0 patients), and stomatitis or oral mucositis (13 patients [15.5%] vs 0 patients).One patient receiving paclitaxel plus alisertib died of sepsis.

Current and Future Therapies for Immunogenic Cell Death and Related Molecules to Potentially Cure Primary Breast Cancer

“…The inhibition of aurora kinase A (AURKA), one of the four switch genes identified, inhibited tumor growth via apoptosis similarly in all tumor subtypes in in vitro and in vivo experiments [ 134 ]. A recent randomized clinical trial showed that the weekly administration of paclitaxel with alisertib based on elevated AURKA expression significantly improved the PFS of patients with metastatic HR-positive and HER-2-negative breast cancer compared with the use of paclitaxel alone; the efficacy of this treatment in patients with TN breast cancer was not examined due to late enrollment [ 135 ]. Alisertib has been shown to alter the immunosuppressive state by eliminating MDSCs via apoptosis and to enhance antitumor immunity by increasing CD8+ and CD4+ T cell abundance, leading to the regression of mouse mammary tumors [ 136 ].…”

Perspective Chapter: Appraisal of Paclitaxel (Taxol) Pros and Cons in the Management of Cancer – Prospects in Drug Repurposing

“…Zhu et al [41] explained in his journal that paclitaxel in combination with immunotherapy can increase the efficacy of treatment against breast cancer by inhibiting the normal function of Tregs and thus reversing the immune escape of tumors. O'Shaughnessy et al [42] performed a randomized clinical trial including 139 patients and suggested that paclitaxel in combination with alisertib improves progression-free survival observed in patients with ER-positive, ERBB2-negative or triple-negative metastatic breast cancer which had been pretreated with endocrine therapy. Markman et al [43] evaluated the activity of single agent weekly paclitaxel in patients with both platinum and paclitaxel (delivered every 3 weeks)-resistant ovarian cancer.…”

Advancements in the Treatment of Triple-Negative Breast Cancer: A Narrative Review of the Literature

“…Recent studies have uncovered that Aurora kinase dysregulation is associated with carcinogenesis and confers tumor cell radio- and chemoresistance [ 46 ]. ENMD-2076 and alisertib are Aurora kinase inhibitors that are currently under investigation for the treatment of TNBC [ 47 , 48 ].…”

“…In mTNBC, alisertib has shown increased mPFS compared to the paclitaxel group [10.2 months vs. 7.1 months; HR: 0.56 (0.37-0.84), p=0.005]. Alisertib was also associated with a higher mOS than paclitaxel alone [26.3 months vs. 25.1 months; HR: 0.89 (0.58-1.38), p=0.61], albeit it was not statistically significant [ 48 ].…”