Key Points
Question
What is the effect of alisertib when added to paclitaxel in the treatment of patients with estrogen receptor–positive, ERBB2-negative or triple-negative metastatic breast cancer?
Findings
In this randomized clinical trial including 139 patients, the addition of oral alisertib to a reduced dose of weekly paclitaxel significantly improved progression-free survival compared with paclitaxel alone, and toxic effects with paclitaxel plus alisertib were manageable with alisertib dose reduction.
Meaning
These findings suggest that in patients with estrogen receptor–positive, ERBB2-negative metastatic breast cancer, the addition of alisertib to paclitaxel is promising and worthy of further study.
This randomized clinical trial compares paclitaxel alone vs paclitaxel plus alisertib for patients with estrogen receptor–positive, ERBB2-negative or triple-negative 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 Participants
In this randomized clinical trial conducted with the US Oncology Network, participants were randomized to intravenous (IV) paclitaxel 90 mg/m2 on days 1, 8, and 15 on a 28-day cycle or IV paclitaxel 60 mg/m2 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 treatment-free interval from neo or adjuvant taxane therapy, and with measurable or evaluable lytic bone-disease. 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) months with 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.
Conclusions and Relevance
This randomized clinical trial found that the addition of oral alisertib to a reduced dose of weekly paclitaxel significantly improved PFS compared with paclitaxel alone, and toxic effects with paclitaxel plus alisertib were manageable with alisertib dose reduction. These data support further evaluation of alisertib in patients with ER-positive, ERBB2-negative MBC.
Trial Registration
ClinicalTrials.gov Identifier: NCT02187991
Introduction
Breast cancer is a heterogeneous disease, with distinct subtypes defined by expression of hormone receptors and human epidermal growth factor receptor 2 (ERBB2, formerly HER2), as well as by gene expression profiles.1,2,3 Novel therapies that inhibit the function of other proteins that triple-negative (TN) and high-grade estrogen receptor (ER)–positive, ERBB2-negative breast cancer are dependent on are greatly needed.
Aurora kinase A (AURKA) is a serine/threonine kinase that regulates the transition from G2 to mitosis and is itself regulated by the proproliferative cell cycle transcription factor, FOXM1.4 AURKA transactivates the FOXM1 promoter and stabilizes FOXM1 in late M phase and early G1 phase of the cell cycle, thus promoting proliferation in TN breast cancer.4 AURKA overexpression in human cancers has been correlated with increased aneuploidy and centrosome amplification.5 Genomic instability can be induced in several cancers, including breast cancer, by increasing the level of AURKA. Results of whole genome and RNA sequencing of TN metastatic breast cancer (MBC) demonstrated cooverexpression of FOXM1 and AURKA in TN MBCs, in association with other markers of rapid proliferation.6 In addition, AURKA was reported to phosphorylate yes-associated protein and to promote yes-associated protein–mediated transcription in TN MBC.7 A study of archival formalin-fixed paraffin-embedded TN breast cancer tissue has also shown overexpression of FOXM1 and AURKA.8 Overexpression of AURKA has been shown to be prognostic in both of ER-positive, EBBR2-negative and TN breast cancer subtypes. Two retrospective studies9,10 showed that high expression of AURKA was associated with shorter recurrence-free and overall survival (OS) in patients with early stage TN or ER-positive, ERBB2-negative breast cancer.
Alisertib (MLN8237) is an adenosine triphosphate–competitive and reversible inhibitor of AURKA with an in vitro inhibition constant (Ki) of 0.43 nM. Alisertib has been evaluated 2 single-agent phase 1 or phase 2 studies11,12 in adults with solid tumors, and the drug proved to inhibit the interaction between N-myc and its stabilizing factor AURKA, inhibiting N-myc signaling and suppressing tumor growth.13 Treatment of tumor cell lines with alisertib induced phenotypes consistent with AURKA inhibition, including mitotic spindle defects, mitotic delay, and apoptosis.14,15,16,17 Synergistic or additive effects have been observed in breast cancer xenograft models when alisertib was added to paclitaxel.18 In addition, alisertib inhibited P-glycoprotein–mediated efflux of paclitaxel in a cell culture model.19 The combination of paclitaxel with alisertib has also been investigated in a phase 1 study in patients with locally advanced or metastatic ovarian or breast cancer, with evidence of activity in both tumor types, including 6 partial responses and 3 stable disease in 11 patients with MBC.20 Adverse events (AEs) observed with alisertib in combination with paclitaxel included stomatitis, neutropenia, leukopenia, anemia, fatigue, diarrhea, headache, and nausea.8,9,20,21
This randomized, phase 2 study assessed the effectiveness and safety of adding alisertib to weekly paclitaxel therapy in patients with ER-positive, ERBB2-negative or TN MBC. The primary objective of the study was to demonstrate the superiority of paclitaxel plus alisertib compared with paclitaxel alone in progression-free survival (PFS) in 2 MBC cohorts.
Methods
This randomized clinical trial was reviewed and approved by the US Oncology institutional review board (Trial Protocol in Supplement 1). Written informed consent was obtained from all eligible patients prior to any screening procedures. All patients signed the Health Insurance Portability and Accountability Act release form. Patient race/ethnicity was collected from information reported in the electronic medical record through a combination of treating physician and participant self-assessment. This study is reported following the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline.
This phase 2 randomized clinical trial with a concurrent control arm was designed to demonstrate superior PFS with paclitaxel plus alisertib compared with paclitaxel alone in patients with ER-positive, ERBB2-negative or TN MBC. The study also assessed the safety of paclitaxel plus alisertib, compared the objective response rates (ORR), complete response (CR), partial response (PR), and clinical benefit rate (CBR; defined as CR + PR + stable disease ≥6 months) associated with paclitaxel plus alisertib vs paclitaxel alone, and assessed the OS in each of the treatment arms in 2 separate patient cohorts (ER-positive, ERBB2-negative and TN). In addition, the patients’ primary or metastatic formalin-fixed, paraffin-embedded breast cancer tissue was archived to identify potential biomarkers associated with alisertib benefit.
Eligible patients were postmenopausal women aged 18 years or older with metastatic or unresectable locally recurrent breast cancer that was histologically confirmed as ER-positive, ERBB2-negative invasive breast cancer (any progesterone receptor status), with Ki-67 greater than 15% in primary or metastatic tissue, or grade 3 TN MBC, to enrich for more highly proliferative cancers that may be more dependent on AURKA. ERBB2-negative was defined as immunohistochemistry status of 0, 1 or more, or 2 or more (if immunohistochemistry ≥2, negative results on a fluorescence in situ hybridization test were required with a ratio <2.0 and a mean ERBB2 copy number <4.0 signals/cell). ER-negative and progesterone receptor–negative status was defined as ER and progesterone receptor less than 1% nuclei positive by immunohistochemistry. Patients may have been treated with 0 or 1 chemotherapy regimen for advanced disease and with neo or adjuvant taxane therapy at least 12 months before the development of metastatic disease. An Eastern Cooperative Group performance status of 0 or 1 and adequate hematologic, cardiac, renal, and liver function were required. Eligible patients were required to have measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1 criteria, or lytic or mixed blastic or lytic bone-only disease. Patients with untreated or progressing brain metastases or those who required corticosteroids were not eligible.
Patients were randomized to receive paclitaxel 60 mg/m2 intravenously (IV) on days 1, 8, and 15 plus alisertib 40 mg twice daily on days 1 to 3, 8 to 10, and 15 to 17 of a 28-day cycle or to single-agent paclitaxel 90 mg/m2 IV on days 1, 8, and 15 of a 28-day cycle at the physician’s office. This dose and schedule of paclitaxel was chosen based on the feasibility of combining paclitaxel with a targeted therapy, bevacizumab, in the Eastern Cooperative Group 2100 first-line MBC.22 Administration of 5 µg/kg of filgrastim was allowed for treatment-limiting neutropenia, and loperamide was used to treat diarrhea but was not allowed prophylactically in cycle 1.
Computed tomography (CT) of chest, abdomen, and pelvis was performed at screening. Chest and abdominal CT imaging were then performed every 8 weeks after initiation of treatment for the first 32 weeks of treatment and every 12 weeks thereafter for the duration of treatment, and at end of treatment. Pelvic CT imaging was obtained at subsequent tumor assessments only if pelvic metastases were identified at screening. Bone scans were obtained on all patients at screening and then every 12 weeks in patients with bone metastases on their baseline bone scan.
Safety was assessed throughout the study. AEs were graded and reported according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.
Statistical Analysis
This open-label, phase 2 randomized clinical trial was conducted to study the effectiveness of alisertib plus paclitaxel in improving PFS compared with paclitaxel alone in 2 separate cohorts of patients with MBC, either ER-positive, ERBB2-negative or TN MBC or unresectable, locally recurrent breast cancer. Patients were stratified as ER-positive, ERBB2-negative cohort and TN cohort based on results of ER, progesterone receptor, and ERBB2 measurements on their metastatic tissue, or, if not available, on their primary breast cancer tissue. For each cohort, a blocked randomization table with the block size of 4 was created by the US Oncology Research biostatistician, and patients were randomly assigned to receive either paclitaxel alone or paclitaxel plus alisertib.
It was estimated that median PFS in patients with TN and ER-positive, ERBB2-negative MBC treated with paclitaxel alone would be 6 months for first-line treatment and 3.5 months for second-line treatment. Using a 2-stage, sequential design with futility boundaries for each group, 112 patients with TN MBC and 140 patients with ER-positive, ERBB2-negative were required to demonstrate a hazard ratio of 0.6 with 80% power and 1-sided α of 5% for PFS with the addition of alisertib to paclitaxel in each of the 2 cohorts. The TN and ER-positive, ERBB2-negative cohorts were analyzed independently, and no change to the statistical plan was made based on the underaccrual to the TN group.
Patients’ baseline demographic and disease characteristics were summarized for the intent-to-treat population, which included all patients registered on study and were described by means with SDs and medians with ranges for continuous variables and by numbers with percentages for categorical variables. PFS was defined as the time from date of registration in the study to the date of first progression of disease or the date of death. Patients whose disease had not progressed were censored at the last contact date. OS was measured from the date of registration to the date of death. PFS and OS were estimated using Kaplan-Meier methods with 95% CIs in the intent-to-treat population and compared by log-rank tests.
The protocol-defined evaluable population included all eligible patients who received at least 1 dose of study drug. CBR and ORR were examined using univariate and multivariate approaches with Fisher exact tests and the logistic regression models. The 95% CIs were estimated for CBR and ORR assuming binomial distribution. A χ2 test was used to estimate the differences between CBRs and ORRs in the 2 arms.
Incidence and grades of AEs for all patients were analyzed using the safety population which included all patients (eligible and ineligible) who received at least 1 dose of study drug. Toxic effects were reported and tabulated by numbers and frequencies for all related AEs. SAS statistical software version 9.4 (SAS Institute) was used for all data analysis. Data were analyzed from from March through May 2019.
Results
Between February 2015 and February 2018, a total of 174 women were enrolled in the trial and were randomly assigned to paclitaxel alone (86 patients), or paclitaxel plus alisertib (88 patients) cohorts. Only women were included in the trial, as MBC is very rare among men, and the safety and efficacy of combination therapy strategies is poorly understood in this population. The trial enrolled 139 patients with ER-positive, ERBB2-negative disease, with 70 randomized to paclitaxel and 69 randomized to paclitaxel plus alisertib. The TN cohort closed with only 35 patients enrolled owing to slow accrual (Figure 1). In the ER-positive, ERBB2-negative group, the patient characteristics were well balanced between the 2 treatment arms (Table 1). The median (range) age was 62 (27-84) years, with 82 patients (59.0%) older than 65 years. A total of 42 patients (30.2%) had received prior chemotherapy for metastatic disease, 57 patients (41.0%) had received prior neo or adjuvant taxane therapy, and 75 patients (54.0%) had a disease-free interval of 5 or more years. Overall, 126 patients (90.6%) had been previously treated with an aromatase inhibitor, 40 patients (28.8%) had been treated with fulvestrant, 44 patients (31.7%) had been treated with tamoxifen, 19 patients (13.7%) had been treated with everolimus, and 28 patients (20.1%) had been treated with palbociclib. The main sites of metastatic disease were bone and liver. There were 3 patients who did not receive any study drug owing to prolonged thrombocytopenia, withdrawal of consent, or new brain metastases.
Figure 1. Patient Recruitment Flowchart .
ER indicates estrogen receptor.
Table 1. Demographic and Baseline Characteristics of the Estrogen Receptor–Positive, ERBB2-Negative Cohort (Intent-to-Treat Population).
| Parameter | No. (%) | |
|---|---|---|
| Paclitaxel plus alisertib (n = 69) | Paclitaxel (n = 70) | |
| Age, median (range), y | 62.5 (33.1-83.4) | 63.2 (26.9-84.2) |
| Race/ethnicity | ||
| Asian | 1 (1.4) | 1 (1.4) |
| Black | 7 (10.1) | 6 (8.6) |
| White | 54 (78.3) | 55 (78.6) |
| Hispanic | 6 (8.7) | 6 (8.6) |
| Other | 1 (1.4) | 2 (2.9) |
| ECOG performance status | ||
| 0 | 36 (52.2) | 31 (44.3) |
| 1 | 32 (46.4) | 39 (55.7) |
| Missing | 1 (1.4) | 0 |
| Current histological findings | ||
| Ductal | 45 (65.2) | 47 (67.1) |
| Lobular | 9 (13.0) | 10 (14.3) |
| Mixed ductal and lobular | 2 (2.9) | 2 (2.9) |
| Other | 13 (18.8) | 11 (15.7) |
| Positive nodes at diagnosis, No. | ||
| 0 | 33 (47.8) | 36 (51.4) |
| 1-3 | 20 (29.0) | 20 (28.6) |
| ≥4 | 13 (18.8) | 9 (12.9) |
| Missing | 3 (4.3) | 5 (7.1) |
| Prior chemotherapy for metastatic disease, No. | ||
| 0 | 48 (69.6) | 48 (68.6) |
| 1 | 21 (30.4) | 22 (31.4) |
| Prior neo or adjuvant taxane | ||
| No | 40 (58.0) | 42 (60.0) |
| Yes | 29 (42.0) | 28 (40.0) |
| Prior paclitaxel or docetaxel | ||
| Paclitaxel | 17 (24.6) | 12 (17.1) |
| Docetaxel | 16 (23.2) | 20 (28.6) |
| Prior Palbociclib for MBC | 16 (23.2) | 14 (20) |
| Disease-free interval (in patients with non-de novo MBC), y | ||
| <5 | 24 (46.2) | 22 (44.9) |
| ≥5 | 28 (53.8) | 27 (55.1) |
| Site of metastasis | ||
| Bone | 45 (65.2) | 55 (78.6) |
| Lymph node or soft tissue | 25 (36.2) | 23 (32.9) |
| Visceral | ||
| Liver | 39 (56.5) | 36 (51.4) |
| Lung | 15 (21.7) | 19 (27.1) |
| Others | 8 (11.6) | 13 (18.6) |
| Peritoneum | 0 | 1 (1.4) |
| Brain | 1 (1.4) | 1 (1.4) |
| Bone only | 9 (13.0) | 9 (12.9) |
Abbreviations: ECOG, Eastern Cooperative Group; MBC, metastatic breast cancer.
The patient characteristics for the patients with TN MBC are summarized in eTable 1 in Supplement 2. Median (range) age was 65 (27-84) years, 11 patients (31.4%) had received prior chemotherapy for metastatic disease, 23 patients (65.7%) had received neo or adjuvant taxane therapy, and 17 patients (58.6%) had a disease-free interval less than 5 years. Two patients never received study treatment owing to a local recurrence or hospitalization.
In the patients with ER-positive, ERBB2-negative MBC, the median (IQR) PFS was 10.2 (3.8-15.7) months with paclitaxel plus alisertib vs 7.1 (3.8-10.6) months with paclitaxel alone (HR, 0.56; 95% CI, 0.37-0.84; P = .005) (Figure 2). The estimated PFS at 12 months was 44.0% (95% CI, 30.9%-56.3%) with paclitaxel plus alisertib and 15.4% (95% CI, 7.3%-26.1%) with paclitaxel alone. With a median (IQR) follow-up time of 22 (10.6-25.1) months, the median (IQR) OS was 26.3 (12.4-37.2) months with paclitaxel plus alisertib vs 25.1 (11.0-31.4) months with paclitaxel alone (HR, 0.89; 95% CI, 0.58-1.38; P = .61). In 30 patients who had been previously treated with palbociclib for MBC, the median (IQR) PFS with paclitaxel alone was 5.6 (3.0-10.6) months (16 patients) and with paclitaxel plus alisertib was 13.9 (5.6-15.6) months (14 patients) (HR, 0.58; 95% CI, 0.26-1.32; P = .19). The CBR observed with paclitaxel plus alisertib in patients who had been pretreated with palbociclib was 61.5% (95% CI, 31.6%-86.1%) vs 37.5% (95% CI, 15.2%-64.6%) in patients who had received paclitaxel alone.
Figure 2. Estimates of Progression-Free Survival in the Estrogen Receptor–Positive, ERBB2-Negative Intent-to-Treat Population.
HR indicates hazard ratio.
In the ER-positive, ERBB2-negative cohort, the ORR was 31.0% (95% CI, 19.5%-44.5%) in the paclitaxel plus alisertib group vs 33.9% (95% CI, 22.3%-47.0%) in the paclitaxel alone group (Table 2). The CBR was 67.2% (95% CI, 53.7%-79.0%) in the paclitaxel plus alisertib arm and 56.5% (95% CI, 43.3%-69.0%) in the paclitaxel alone group (Table 2).
Table 2. Overall Response Rates by Study Treatment in the Estrogen Receptor–Positive, ERBB2-Negative Cohort.
| Best overall response | Paclitaxel plus alisertib (n = 58) | Paclitaxel (n = 62) | ||
|---|---|---|---|---|
| No. (%) | 95% CI, % | No. (%) | 95% CI, % | |
| CR | 1 (1.7) | 0-9.2 | 0 | NA |
| PR | 17 (29.3) | 18.1-42.7 | 21 (33.9) | 22.3-47.0 |
| Objective response ratea | 18 (31.0) | 19.5-44.5 | 21 (33.9) | 22.3-47.0 |
| Stable disease | 35 (60.3) | 46.6-73.0 | 33 (53.2) | 40.1-66.0 |
| ≥6 mo | 21 (36.2) | 24.0-49.9 | 14 (22.6) | 12.9-35.0 |
| Clinical benefit rateb | 39 (67.2) | 53.7-79.0 | 35 (56.5) | 43.3-69.0 |
| Progression of disease | 5 (8.6) | 2.9-19.0 | 8 (12.9) | 5.7-23.9 |
Abbreviations: CR, complete response; NA, not applicable; PR, partial response.
Calculated as CR + PR. P > .05 between intervention and control.
Calculated as CR + PR + stable disease at 6 months. P > .05 between intervention and control.
Among 35 patients with TN MBC, the median (IQR) PFS was 9.6 (6.1-22.6) months with paclitaxel plus alisertib vs 5.7 (2.9-8.2) months with paclitaxel alone (HR, 0.35; 95% CI, 0.14-0.89; P = .02) (eFigure in Supplement 2). With a median (IQR) follow-up of 13.7 (7.5-23.7) months, the median (IQR) OS was 16 (9.6-34.0) months with paclitaxel plus alisertib vs 12.7 (6.8-23.5) months with paclitaxel alone (HR, 0.51; 95% CI, 0.23-1.13; P = .09). The ORRs and CBRs in the evaluable patients with TNBC are summarized in eTable 2 in Supplement 2.
In the ER-positive, ERBB2-negative group treated with paclitaxel alone, 22 patients (31.4%) had a dose delay and dose reduction, while 41 patients (62.1%) had an alisertib dose delay and reduction and 42 patients (63.6%) had a paclitaxel dose delay in the paclitaxel plus alisertib group (eTable 3 in Supplement 2). Similar findings were observed in the patients with TN MBC.
Most of the AEs in all patients combined were grade 1 or 2. 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), stomatitis or oral mucositis (13 patients [15.5%] vs 0 patients) and neuropathy (1 patient [1.5%] vs 8 patients [11.4%]) (Table 3). Most of the serious AEs occurred in the paclitaxel plus alisertib group and included diarrhea (3 patients [4.5%]), febrile neutropenia (3 patients [4.5%]), sepsis (3 patients [4.5%]) or any of nausea, chest pain, peripheral neuropathy, pulmonary embolism, or respiratory infection (2 patients [3.0%] combined). One patient died from sepsis during paclitaxel plus alisertib treatment. A total of 29 patients (43.9%) with paclitaxel plus alisertib and 11 patients (15.7%) with paclitaxel alone received standard-dose (5 µg/kg) filgrastim.
Table 3. Treatment-Related Toxic Effects in Both Cohorts.
| Reported term | Patients, No. (%) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Paclitaxel plus alisertib (n = 66) | Paclitaxel (n = 70) | |||||||||
| Grade 1 | Grade 2 | Grade 3 | Grade 4 | Total | Grade 1 | Grade 2 | Grade 3 | Grade 4 | Total | |
| Neutropenia | 3 (3.6) | 4 (4.8) | 27 (32.1) | 23 (27.4) | 57 (67.9) | 1 (1.2) | 3 (3.5) | 11 (12.9) | 3 (3.5) | 18 (21.2) |
| Anemia | 8 (9.5) | 6 (7.1) | 8 (9.5) | 0 | 22 (26.2) | 5 (5.9) | 5 (5.9) | 1 (1.2) | 0 | 11 (12.9) |
| Leukopenia | 0 | 3 (3.6) | 5 (6.0) | 2 (2.4) | 10 (11.9) | 2 (2.4) | 1 (1.2) | 2 (2.4) | 0 | 5 (5.9) |
| Thrombocytopenia | 3 (3.6) | 0 | 0 | 0 | 3 (3.6) | 0 | 0 | 0 | 0 | 0 |
| Febrile neutropenia | 0 | 0 | 0 | 1 (1.2) | 1 (1.2) | 0 | 0 | 0 | 0 | 0 |
| Diarrhea | 17 (20.2) | 22 (26.2) | 9 (10.7) | 0 | 48 (57.1) | 9 (10.6) | 2 (2.4) | 0 | 0 | 11 (12.9) |
| Nausea | 24 (28.6) | 11 (13.1) | 0 | 0 | 35 (41.7) | 19 (22.4) | 4 (4.7) | 1 (1.2) | 0 | 24 (28.2) |
| Mucositis oral | 7 (8.3) | 7 (8.3) | 9 (10.7) | 0 | 23 (27.4) | 4 (4.7) | 0 | 0 | 0 | 4 (4.7) |
| Stomatitis | 6 (7.1) | 4 (4.8) | 4 (4.8) | 0 | 14 (16.7) | 7 (8.2) | 0 | 0 | 0 | 7 (8.2) |
| Fatigue | 21 (25.0) | 17 (20.2) | 4 (4.8) | 0 | 42 (50.0) | 26 (30.6) | 6 (7.1) | 2 (2.4) | 0 | 34 (40.0) |
| Neuropathy | 7 (10.6) | 4 (6.1) | 1 (1.5) | 0 | 12 (18) | 9 (12.9) | 8 (11.4) | 8 (11.4) | 0 | 25 (35.7) |
| Dizziness | 7 (8.3) | 2 (2.4) | 0 | 0 | 9 (10.7) | 2 (2.4) | 0 | 0 | 0 | 2 (2.4) |
| Headache | 9 (10.7) | 2 (2.4) | 0 | 0 | 11 (13.1) | 4 (4.7) | 1 (1.2) | 0 | 0 | 5 (5.9) |
Discussion
In this randomized clinical trial, patients received a lower-than-standard dose of weekly paclitaxel in combination with 3 days per week of alisertib to maximize concomitant exposure of alisertib and paclitaxel while providing treatment-free periods for recovery from neutropenia. The same drug doses were found to be feasible to administer in a phase 1 paclitaxel plus alisertib dose escalation study by Falchook et al21 in patients with previously treated metastatic or locally recurrent ovarian or breast cancer.
The AURKA gene is amplified or overexpressed in many tumor types, including breast cancer, and these alterations are associated with the development of metastases, chemotherapy resistance, and worse survival.23 Several studies have assessed the function of AUKRA in breast cancer.12,20,21,24 In an in-depth comparison of a panel of proliferation markers in 3093 women with breast cancer by Ali et al,25 AURKA out-performed other proliferation markers, including Ki-67, as an independent factor associated with breast cancer–specific survival in patients with ER-positive breast cancer. Breast cancer cells that overexpress AURKA demonstrate chemoresistance that can be overcome with the selective Aurora kinase A inhibitor, alisertib.24
This phase 2 randomized clinical trial in 139 patients with ER-positive, ERBB2-negative MBC demonstrated a significant improvement in median PFS from 7.1 months with paclitaxel alone to 10.2 months when alisertib was added to paclitaxel. This 3-month improvement in PFS is similar to that identified by Falchook et al26 in the randomized phase 2 study of paclitaxel plus alisertib in patients with advanced breast cancer or recurrent ovarian cancer where the median PFS was 2 months longer in the paclitaxel plus alisertib group vs the paclitaxel alone group (6.7 months vs 4.7 months).26 The PFS curves in the ER-positive, ERBB2-negative population separated at 6 months in our study, as well as the Falchook et al trial,26 suggesting that alisertib may delay the development of acquired resistance to paclitaxel.
A phase 1 trial by Hadad et al27 evaluated combined alisertib plus fulvestrant in postmenopausal patients with endocrine therapy–resistant ER-positive MBC. Alisertib was given at 50 mg twice daily on days 1 to 3, 8 to 10, and 15 to 17 of a 28-day cycle, along with standard-dose fulvestrant. The combination proved to be well tolerated, and the 6-month CBR of 78% and median PFS of 12.4 months were important findings in an endocrine therapy–resistant population. A follow-up phase 2 randomized clinical trial by Haddad et al28 in 90 patients with ER-positive, ERBB2-negative MBC who had previously undergone endocrine therapy and CDK 4/6 inhibitor treatment reported a CBR of 42% and median PFS of 5.6 months with alisertib alone and CBR of 29% and median PFS of 5.1 months with alisertib plus fulvestrant. Patients treated with the combination were more heavily pretreated, potentially explaining the lesser efficacy in this group. The promising CBR in patients who were CDK 4/6 inhibitor-resistant and receiving alisertib alone corroborates the activity of alisertib seen in the patients who had been pretreated with CDK 4/6 inhibitor in this study.
In a phase 2 study of oral alisertib (50 mg twice daily for 7 days in a 21-day cycle), single agent alisertib had a manageable toxic effects profile and an ORR of 18% in patients with ER-positive or ERBB2-positive breast cancer who were resistant to endocrine therapy, but alisertib had minimal single agent activity in patients with TN MBC.12 Conversely, alisertib significantly enhanced the antitumor activity of paclitaxel and docetaxel in preclinical TNBC models and delayed tumor regrowth after discontinuation of alisertib.18 In this randomized clinical trial, the paclitaxel plus alisertib combination was associated with a median PFS of 9.6 months and a CBR of 81% in the small, underpowered TN MBC cohort.
With a median (range) of 5 (1-30) cycles of alisertib delivered in the patients with ER-positive, ERBB2-negative MBC, 70% of patients required a dose reduction in alisertib, and 81% had at least 1 grade 3 or 4 AE with the combination. Treating physicians were advised to hold alisertib if patients developed stomatitis or diarrhea in the context of paclitaxel plus alisertib–induced neutropenia to minimize these toxic effects. With this, the rates of febrile neutropenia, high grade neutropenia, stomatitis, and diarrhea with the combination were low and similar to those reported in other paclitaxel plus alisertib trials.12,26,29
Limitations
This study has some limitations. First, poor accrual to the TN MBC cohort, likely owing to the paclitaxel alone control arm, precludes reliable interpretation of the limited data obtained in this trial. In addition, ER-positive, ERBB2-negative MBC is a heterogeneous disease, and this study does not provide insight into how to identify patients who may benefit from adding alisertib to paclitaxel, as well as those who may not benefit. The lack of correlative biomarker information at present is also a limitation, and this will be addressed in the near future.
Conclusions
The findings of this randomized clinical trial suggest that, given the improvement in PFS observed in patients with ER-positive, ERBB2-negative MBC who had been pretreated with endocrine therapy, the combination of alisertib plus paclitaxel warrants further evaluation in a larger confirmatory trial in patients with endocrine therapy–resistant MBC. In addition, the ease of dosing alisertib orally 3 days per week may allow it to be combined with oral taxanes in future trials.
Trial Protocol and Statistical Analysis Plan
eFigure. Estimates of Progression-Free-Survival for Patients With Triple-Negative Metastatic Breast Cancer Receiving Paclitaxel or Paclitaxel Plus Alisertib (Intent-to-Treat Population)
eTable 1. Demographic and Baseline Characteristics for Triple-Negative Metastatic Breast Cancer Cohort (Intent-to-Treat Population)
eTable 2. Overall Response Rate by Study Treatment in Triple-Negative Metastatic Breast Cancer Cohort (Evaluable Population)
eTable 3. Summary of Drug Exposure in Estrogen Receptor-Positive, ERBB2-Negative Cohort (Safety Population)
Data Sharing Statement
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol and Statistical Analysis Plan
eFigure. Estimates of Progression-Free-Survival for Patients With Triple-Negative Metastatic Breast Cancer Receiving Paclitaxel or Paclitaxel Plus Alisertib (Intent-to-Treat Population)
eTable 1. Demographic and Baseline Characteristics for Triple-Negative Metastatic Breast Cancer Cohort (Intent-to-Treat Population)
eTable 2. Overall Response Rate by Study Treatment in Triple-Negative Metastatic Breast Cancer Cohort (Evaluable Population)
eTable 3. Summary of Drug Exposure in Estrogen Receptor-Positive, ERBB2-Negative Cohort (Safety Population)
Data Sharing Statement