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Sapanisertib Plus Exemestane or Fulvestrant in Women with Hormone Receptor-Positive/HER2-Negative Advanced or
Bora Lim1, David A Potter2, Mohamad A Salkeni3
1M.D. Anderson Cancer Center, Houston, Texas. Bora.Lim@bcm.edu jennifer.diamond@cuanschutz.edu.
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 hormone receptor-positive (HR+)/HER2-negative (HER2-) advanced/metastatic breast cancer.
Patients And Methods:
Eligible patients had previously progressed on everolimus with exemestane/fulvestrant and received ≤3 (phase IB) or ≤1 (phase II) prior chemotherapy regimens. Patients received sapanisertib 3 to 5 mg every day (phase IB), or 4 mg every day (phase II) with exemestane 25 mg every day 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 dose-limiting toxicities, at sapanisertib doses of 5 mg every day (n = 4) and 4 mg every day (n = 1); sapanisertib 4 mg every day was the MTD 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%, respectively. 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.
Insights
Sapanisertib combined with exemestane or fulvestrant showed clinical benefit in postmenopausal women with advanced hormone receptor-positive breast cancer, even after prior everolimus treatment. The combination was well-tolerated, with AKT1 mutation status potentially predicting response.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Hormone receptor-positive (HR+)/HER2-negative advanced breast cancer remains a significant clinical challenge, particularly after progression on standard therapies like everolimus.
- Targeting the mTOR kinase pathway (mTORC1/2) offers a therapeutic strategy for HR+ breast cancer.
- Dual mTOR inhibitors like sapanisertib represent a novel approach to overcome resistance mechanisms.
Purpose of the Study:
- To evaluate the safety and efficacy of sapanisertib in combination with exemestane or fulvestrant in postmenopausal women with HR+/HER2- advanced/metastatic breast cancer.
- To determine the maximum tolerated dose (MTD) of sapanisertib in combination therapy.
- To assess antitumor activity, including clinical benefit rate (CBR) and overall response rate (ORR), stratified by prior response to everolimus.
Main Methods:
- An open-label, multicenter, phase IB/II study enrolled 118 postmenopausal women with pretreated HR+/HER2- advanced/metastatic breast cancer.
- Patients received sapanisertib (3-5 mg daily in Phase IB, 4 mg daily in Phase II) plus exemestane (25 mg daily) or fulvestrant (500 mg monthly).
- Phase II included parallel cohorts based on prior everolimus sensitivity; the primary endpoint was CBR at 16 weeks.
Main Results:
- Sapanisertib 4 mg daily was identified as the MTD when combined with exemestane or fulvestrant.
- In Phase II, the CBR-16 was 45% in everolimus-sensitive cohorts versus 23% in everolimus-resistant cohorts; ORRs were 8% and 2%, respectively.
- Molecular analysis indicated a positive association between AKT1 mutation status and treatment response (P=0.0262). Common adverse events included nausea, fatigue, and diarrhea.
Conclusions:
- The combination of sapanisertib with exemestane or fulvestrant is well-tolerated and demonstrates clinical benefit in pretreated patients with HR+/HER2- advanced breast cancer.
- The regimen shows activity in both everolimus-sensitive and everolimus-resistant populations, suggesting potential utility across different resistance profiles.
- Further investigation into predictive biomarkers, such as AKT1 mutations, may help optimize patient selection for this therapeutic strategy.
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