Sapanisertib, a dual mTORC1/2 inhibitor, may offer more complete inhibition of the PI3K/AKT/mTOR pathway than mTORC1 inhibitors, such as everolimus. This phase II study evaluated the efficacy and safety of single-agent sapanisertib and sapanisertib plus the PI3Kα inhibitor TAK-117, vs. everolimus in patients with advanced clear cell renal cell carcinoma (ccRCC) that had progressed on or after VEGF-targeted therapy.
Patients with histologically confirmed, advanced ccRCC were randomized 1:1:1 to receive single-agent everolimus 10 mg once daily, single-agent sapanisertib 30 mg once weekly, or sapanisertib 4 mg plus TAK-117 200 mg, both once daily for 3 days/week, in 28-day cycles. The primary endpoint was progression-free survival (PFS).
Ninety-five patients were treated with everolimus or sapanisertib (n = 32 each), or sapanisertib plus TAK-117 (n = 31). There were no significant differences in PFS among the 3 groups or across any subgroups. Median PFS was 3.8 months with everolimus vs. 3.6 months with sapanisertib (HR, 1.33; 95% CI, 0.75-2.36), and 3.1 months with sapanisertib plus TAK-117 (HR, 1.37; 95% CI, 0.75-2.52). No significant differences in overall survival were seen among groups. Overall response rate was 16.7%, 0%, and 7.1%, respectively. Discontinuations due to treatment-emergent adverse events were 15.6%, 28.1%, and 29.0%.
Sapanisertib with or without TAK-117 was less tolerable and did not improve efficacy vs. everolimus in patients with advanced ccRCC who had relapsed after or were refractory to VEGF-targeted therapies. Dual mTORC1/2 inhibition may not be an effective therapeutic approach for these patients.
The oncologist. 2022 Sep 23 [Epub ahead of print]
Toni Choueiri, Camillo Porta, Cristina Suárez, John Hainsworth, Eric Voog, Ignacio Duran, James Reeves, Piotr Czaykowski, Daniel Castellano, Jingjing Chen, Farhad Sedarati, Thomas Powles
Dana-Farber Cancer Institute, Boston, MA, USA., University of Pavia and IRCCS San Matteo University Hospital Foundation, Pavia, Italy., Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall d´Hebron, Vall d´Hebron Barcelona Hospital Campus, Barcelona, Spain., Sarah Cannon Research Institute, Nashville, TN, USA., Centre Jean Bernard/Clinique Victor Hugo, Institut Inter-régional de Cancérologie, Le Mans, France., Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Cantabria, Spain., Florida Cancer Specialists/Sarah Cannon Research Institute, Fort Myers, FL, USA., CancerCare Manitoba, Winnipeg, Manitoba, Canada., i+12 Research Institute, Hospital Universitario 12 de Octubre, Madrid, Spain., Takeda Development Center Americas, Inc., Lexington, MA, USA., Barts Cancer Institute, Royal Free NHS Trust, St. Bartholomew's Hospital, London, UK.