Alisertib Did Not Restore Fulvestrant Sensitivity Among Patients With Endocrine-Resistant, HER2-Negative Breast Cancer

The addition of fulvestrant to alisertib treatment did not cause a statistically significant increase of objective response rate or progression-free survival for patients with endocrine-resistant, HER2-negative metastatic breast cancer, according to results of a phase 2 clinical trial.

“Effective approaches to overcome [ET] resistance remain a major challenge in [ER+] breast cancer management,” Tufia Haddad, MD, Department of Oncology, Mayo Clinic, Rochester, Minnesota, and colleagues explained. In this study, the authors wrote, they sought to determine if treatment with alisertib could “restore fulvestrant sensitivity and improve tumor objective response rates compared with alisertib monotherapy” among patients with endocrine-resistant metastatic breast cancer.

The phase 2 TBCRC041 clinical trial enrolled 96 postmenopausal patients with endocrine-resistant, HER2-negative metastatic breast cancer from July 2017 to November 2019. Patients were randomized on a 1-to-1 basis to receive either 50mg alisertib twice daily on days 1 to 3, 8 to 10, and 15 to 17 of a 28-day cycle (monotherapy arm, n = 46); or alisertib plus 500mg fulvestrant on days 1 and 15 of cycle 1 and day 1 of all following cycles (combination arm, n = 45). The primary end point of this study was improvement of the ORR in the combination arm, at least 20% greater than the monotherapy arm, with an expected ORR for the monotherapy arm of 20%. Secondary end points included 24-week clinical benefit rate and progression-free survival.

All of the 91 evaluable patients had received prior treatment with CDK 4/6 inhibitors. In the monotherapy arm, the ORR was 19.6%; (90% confidence interval [CI], 10.6% to 31.7%) vs 20% (90% CI, 10.9% to 32.3%) in the combination arm. The median PFS was 5.6 months (95% CI, 3.9 to 10 months) in the monotherapy arm compared to 5.4 months (95% CI, 3.9 to 7.8 months) in the combination arm. The 24-week clinical benefit rate of the monotherapy arm was 41.3% (90% CI, 29.0% to 54.5%) vs 28.9% (90% CI, 18.0% to 42.0%) in the combination arm.

The most common grade ≥3 adverse events in the monotherapy arm were neutropenia (43.4%), leukopenia (17.4%), and anemia (19.6%). The most common grade ≥3 adverse events in the combination arm were neutropenia (42.4%), leukopenia (31.1%), lymphopenia (15.6%), fatigue (11.1%), and anemia (8.9%). The most common reason for discontinuation was disease progression – experienced by 38 patients (82.6%) in the monotherapy arm and 31 patients (68.9%) in the combination arm.

While Dr Haddad and colleagues concluded that adding fulvestrant to treatment with alisertib was not associated with increased ORR or PFS for patients with endocrine-resistant, HER2- metastatic breast cancer, they did note that, “promising clinical activity was observed with alisertib monotherapy” among patients with endocrine-resistant and CDK 4/6i-resistant metastatic breast cancer, and this clinical activity could warrant further study.

Source:                                        

Haddad TC, Suman VJ, D'Assoro AB, et al. Evaluation of alisertib alone or combined with fulvestrant in patients with endocrine-resistant advanced breast cancer: the phase 2 TBCRC041 randomized clinical trial. JAMA Oncol. Published online: March 9, 2023. doi:10.1001/jamaoncol.2022.7949