Sapanisertib Plus Exemestane or Fulvestrant in Women with Hormone Receptor-Positive/HER2-Negative Advanced or Metastatic Breast Cancer
Mené sur 118 patientes atteintes d'un cancer du sein HR+ HER2- de stade avancé ou métastatique, cet essai de phase IB/II évalue l'efficacité, du point de vue du taux de bénéfice clinique en semaine 16, et la dose maximale tolérée du sapanisertib (un inhibiteur de mTORC1 et mTORC2) en combinaison avec l'exémestane ou le fulvestrant
Purpose: This open-label, multicenter, phase IB/II study evaluated sapanisertib, a dual inhibitor of mTOR kinase complexes 1/2, plus exemestane or fulvestrant in postmenopausal women with HR+/HER2- advanced/metastatic breast cancer. Experimental Design: Eligible patients had previously progressed on everolimus with exemestane/fulvestrant and received {less than or equal to}3 (phase IB) or {less than or equal to}1 (phase II) prior chemotherapy regimens. Patients received sapanisertib 3-5 mg once daily (QD) (phase IB), or 4 mg QD (phase II) with exemestane 25 mg QD or fulvestrant 500 mg monthly in 28-day cycles. Phase II enrolled parallel cohorts based on prior response to everolimus. The primary objective of phase II was to evaluate antitumor activity by clinical benefit rate at 16 weeks (CBR-16). Results: Overall, 118 patients enrolled in phase IB (n = 24) and II (n = 94). Five patients in phase IB experienced DLTs, at sapanisertib doses of 5 mg QD (n = 4) and 4 mg QD (n = 1); sapanisertib 4 mg QD was the maximum tolerated dose in combination with exemestane or fulvestrant. In phase II, in everolimus-sensitive versus everolimus-resistant cohorts, CBR-16 was 45% versus 23%, and overall response rate was 8% versus 2%. The most common adverse events were nausea (52%), fatigue (47%), diarrhea (37%), and hyperglycemia (33%); rash occurred in 17% of patients. Molecular analysis suggested positive association between AKT1 mutation status and best treatment response (complete+partial response; P = 0.0262). Conclusions: Sapanisertib plus exemestane or fulvestrant was well tolerated and exhibited clinical benefit in postmenopausal women with pretreated everolimus-sensitive or everolimus-resistant breast cancer.