Alisertib Combination May Boost Metastatic Breast Cancer PFS

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Supplementing weekly paclitaxel chemotherapy with the oral aurora kinase A (AURKA) inhibitor alisertib has extended progression-free survival (PFS) for women with oestrogen receptor (ER)-positive, HER2-negative metastatic breast cancer participating in a phase II trial. 

Joyce O’Shaughnessy, from Baylor University Medical Center in Dallas, Texas, USA, and co-investigators say that the study findings in patients who had previously been treated with endocrine therapy and up to one line of chemotherapy for metastatic disease suggest that “the combination of alisertib plus paclitaxel warrants further evaluation in a larger confirmatory trial” for this population. 

After a median 22.0 months of follow-up, median PFS was 10.2 months for the 69 patients who were randomly assigned to receive alisertib 40 mg twice daily on days 1–3, 8–10 and 15–17 of a 28-day cycle alongside a reduced-dose regimen of paclitaxel 60 mg/m2 on days 1, 8 and 15. 

This was significantly longer than the median 7.1 months achieved by the 70 patients who instead received paclitaxel at the standard 90 mg/m2 dose on days 1, 8 and 15 of each cycle, with a hazard ratio for progression or death of 0.56. 

Noting that the PFS curves of the two treatment groups began to separate at 6 months, the study authors hypothesise in JAMA Network Open “that alisertib may delay the development of acquired resistance to paclitaxel.” 

However, the two treatment arms did not significantly differ with regard to overall survival (median, 26.3 vs 25.1 months), the objective response rate (31.0 vs 33.9%) or the clinical benefit rate, defined as the proportion of patients achieving a complete or partial response or stable disease for at least 6 months (67.2 vs 56.5%). 

And among the 30 patients who had previously received palbociclib for metastatic disease, PFS did not significantly differ between those who received alisertib plus paclitaxel and those given paclitaxel alone (13.9 vs 5.6 months). 

Discussing the safety results, the researchers observe that “[t]reating 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.” 

Overall, 62.1% of patients in the combination arm required both dose delay and reduction of alisertib and 16.7% paclitaxel delay and reduction, as did 31.4% of patients who received only paclitaxel. 

Grade 3–4 adverse events (AEs) occurred in 81% of the combination treatment arm, most commonly neutropenia (59.5 vs 16.4% with paclitaxel alone), stomatitis or oral mucositis (15.5 vs 0.0%), diarrhoea (10.7 vs 0.0%), anaemia (9.5 vs 1.2%) and neuropathy (1.5 vs 11.4%). 

In the combination arm, there were three serious AEs each of diarrhoea, febrile neutropenia and sepsis each, plus two patients affected by a combination of serious AEs. One patient died from sepsis. 

“ER-positive, [HER2]-negative [metastatic breast cancer] 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”, remark Joyce O’Shaughnessy and team. 

Nevertheless, they hope that the PFS findings and “the ease of dosing alisertib orally 3 days per week may allow it to be combined with oral taxanes in future trials.”

Reference 

O’Shaughnessy J, McIntyre K, Wilks S, et al. Efficacy and safety of weekly paclitaxel with or without oral alisertib in patients with metastatic breast cancer. A randomized clinical trial. JAMA Netw Open; 4: e214103. Published online 20 April 2021. doi:10.1001/jamanetworkopen.2021.4103