Sapanisertib Plus Fulvestrant in Post-Menopausal Women with Estrogen Receptor-Positive/HER2-Negative Advanced Breast Cancer After Progression on Aromatase Inhibitor
Mené sur 141 patientes atteintes d'un cancer du sein ER+ HER2- de stade avancé après la ménopause, cet essai de phase II évalue l'efficacité, du point de vue de la survie sans progression, et la toxicité du sapanisertib (un inhibiteur de mTOR) en combinaison avec le fulvestrant, après l'échec d'un traitement par inhibiteurs de l'aromatase
Purpose: This phase II study investigated daily (QD) or weekly (QW) sapanisertib (a selective dual inhibitor of mTOR complexes 1 and 2) in combination with fulvestrant. Experimental Design: Post-menopausal women with estrogen-receptor positive (ER+)/HER2- advanced or metastatic breast cancer following progression during/after aromatase inhibitor treatment were randomized to receive fulvestrant 500 mg (28-day treatment cycles), fulvestrant plus sapanisertib 4 mg QD, or fulvestrant plus sapanisertib 30 mg QW, until progressive disease, unacceptable toxicity, consent withdrawal, or study completion. Results: Among 141 enrolled patients, baseline characteristics were balanced among treatment arms, including prior cyclin dependent kinase-4/6 (CDK4/6) inhibitor treatment in 33-35% of patients. Median progression-free survival (PFS; primary endpoint) was 3.5 months in the single-agent fulvestrant arm, compared with 7.2 months for fulvestrant plus sapanisertib QD (hazard ratio, 0.77; 95% confidence interval, 0.47-1.26) and 5.6 months for fulvestrant plus sapanisertib QW (0.88; 0.53-1.45). The greatest PFS benefits were seen in patients who had previously received CDK4/6 inhibitors. The most common adverse events were nausea, vomiting, and hyperglycemia, all occurring more frequently in the combination therapy arms. Treatment discontinuation due to adverse events occurred more frequently in the two combination therapy arms than with single-agent fulvestrant (32% and 36% versus 4%, respectively). Conclusions: Fulvestrant plus sapanisertib QD/QW resulted in numerically longer PFS in patients with ER+/HER2- advanced or metastatic breast cancer, compared with single-agent fulvestrant. The combination was associated with increased toxicity. Further development of sapanisertib using these dosing schedules in this setting is not supported by these data. Trial Registration: ClinicalTrials.gov: NCT02756364.