Background: Sapanisertib (S) is an investigational, oral, and highly selective adenosine triphosphate (ATP)-competitive inhibitor of target of rapamycin complex 1/2 (TORC1/2). Simultaneous inhibition of ER and phosphoinositide 3kinase (PI3K)/serine/threonine-specific protein kinase (AKT)/mammalian target of rapamycin (mTOR) pathway with S may restore sensitivity to endocrine therapies in patients (pts) with breast cancer, who have progressed during or after aromatase inhibitor (AI) therapy. Here we report data from a phase 2 study of continuous once-daily or once-weekly S + fulvestrant (F) compared with single-agent F in pts with breast cancer. Methods: Postmenopausal women with ER+ and HER2- advanced or metastatic breast cancer following progression during/after AI therapy were randomized 1:1:1 to receive F (500 mg intramuscularly on day 1 of a 28-day cycle) alone (Arm A) or in combination with oral S either daily (4 mg; Arm B) or weekly (30 mg; Arm C) until progressive disease (PD), unacceptable toxicity, or consent withdrawal. Pts were stratified according to presence/absence of visceral metastases, previous sensitivity to hormonal therapy, and previous exposure to cyclin-dependent kinase (CDK) 4/6 inhibitors. Pts on Arm A could receive S at PD. Key exclusion criteria were: prior therapy with mTOR inhibitors, PI3K inhibitors, or F; >1 prior line of chemotherapy for MBC; recurrent disease or PD on >2 endocrine therapies for MBC. The primary endpoint was progression-free survival (PFS). Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR; any duration and at 24 weeks), overall survival (OS), and safety. Results: Between Aug 2016 and May 2018, 141 pts were randomized (Arm A: 46; Arm B: 47; Arm C: 48). One patient in Arm C was not treated. Median age was 58 years (range 33-84). Stratification was well balanced across arms; overall, 65% had visceral metastases, 84% had prior sensitivity to hormonal therapy, and 34% had received prior CDK 4/6 inhibitors. Pts received a median of 4 cycles (range 1-40) of F on Arm A, 5 cycles (range 1-33) of daily S + F on Arm B, and 4 cycles (range 1-39) of weekly S + F on Arm C. The last follow-up visit was in Nov 2019. The main reasons for treatment discontinuation included PD (76%, 60%, 53%; Arm A, B, and C, respectively) and adverse events (AEs; 4%, 32%, 36%; Arm A, B, and C, respectively). Of the pts in Arm A with confirmed PD, 18 crossed over to Arm B and C (9 each); crossover was analyzed separately. Efficacy data are shown in the table; median PFS was 3.5, 7.2, and 5.6 months in Arm A, B, and C, respectively. OS data were immature at the primary data cut-off. Three pts died during the study (2 and 1 in Arm A and B, respectively); all deaths were attributed to underlying disease. Most common any-grade AEs were: asthenia (24%), hyperglycemia, fatigue, and headache (22% each) in Arm A; hyperglycemia (57%) and nausea (49%) in Arm B; nausea (87%) and vomiting (70%) in Arm C. Conclusion: Daily or weekly treatment with S + F demonstrated modest clinical benefit in ER+/HER2- advanced or MBC pts who progressed during/after AI compared with single-agent F. The S + F combinations had increased toxicity leading to more treatment discontinuations compared with single-agent F.

Table: PFS and response data

Arm A Single-agent F (n = 46)Arm B S (QD) + F (n = 47)Arm C S (QW) + F (n = 48)
Median PFS (95% CI), months 3.5 (1.9-5.6) 7.2 (3.9-10.6) 5.6 (4.1-9.0) 
HR (95% CI)  0.77 (0.47-1.26) 0.88 (0.53-1.45) 
ORR*, n/N (%) 5/46 (10.9) 10/47 (21.3) 6/47 (12.8) 
CBR*, n/N (%) 28/46 (60.9) 35/47 (74.5) 31/47 (66.0) 
CBR≥6 months*, n/N (%) 15/46 (32.6) 23/47 (48.9) 12/47 (25.5) 
Arm A Single-agent F (n = 46)Arm B S (QD) + F (n = 47)Arm C S (QW) + F (n = 48)
Median PFS (95% CI), months 3.5 (1.9-5.6) 7.2 (3.9-10.6) 5.6 (4.1-9.0) 
HR (95% CI)  0.77 (0.47-1.26) 0.88 (0.53-1.45) 
ORR*, n/N (%) 5/46 (10.9) 10/47 (21.3) 6/47 (12.8) 
CBR*, n/N (%) 28/46 (60.9) 35/47 (74.5) 31/47 (66.0) 
CBR≥6 months*, n/N (%) 15/46 (32.6) 23/47 (48.9) 12/47 (25.5) 

*Safety population Including 2 complete responses

Citation Format: José Á García-Saenz, Noelia Martínez Jáñez, Miguel Martin, Ainhara Lahuerta Martínez, Santiago González-Santiago, Nieves Ferrer, Manuel Ramos Vázquez, José Luis Alonso Romero, Antonio Antón, Eva Carrasco, Jingjing Chen, Rachel Neuwirth, E Jane Leonard, Dennis Slamon. Open-label, randomized, phase 2 study of sapanisertib (TAK-228/MLN0128) in combination with fulvestrant in postmenopausal women with estrogen receptor-positive (ER+)/human epidermal growth factor receptor-2-negative (HER2-) advanced or metastatic breast cancer (MBC) that previously progressed during or after aromatase inhibitor therapy (NCT02756364) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-01.