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Dual mTOR1/2 Inhibitor Sapanisertib (FTH-003/TAK-228) in Combination With Weekly Paclitaxel in Patients With
Joaquim Bellmunt1, Pablo Maroto2, Teresa Bonfill3
1Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA; Cancer Research Program, Hospital del Mar Research Institute, Barcelona, Spain.
Background:
The PI3K/AKT/mTOR pathway is frequently altered at genomic level in metastatic urothelial carcinoma (mUC). Since mTOR is the last protein in the PI3K signaling cascade, it may have the largest impact on the pathway and has been a focus of targeted therapies. Sapanisertib (FTH-003/TAK-228) is an oral highly selective mTOR1 and mTOR2 inhibitor. NFE2L2 mutations have been described as predictive biomarkers of response in patients with advanced squamous cell lung cancer treated with sapanisertib.
Patients And Methods:
This was an open-label, investigator-initiated phase II study evaluating safety and efficacy of sapanisertib plus paclitaxel in patients with mUC who had progressed to prior platinum therapy, and the correlation with NFE2L2 mutations in responders. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS) and safety. Patients were treated with weekly paclitaxel at dose of 80 mg/m2 on days 1, 8, and 15 in combination with sapanisertib 4 mg administered orally 3 days per week on days 2-4, 9-11, 16-18, and 23-25 of a 28-day cycle. NFE2L2 mutations were analyzed by Sanger sequencing in responders.
Results:
22 patients were enrolled from May 2018 to April 2020; the trial was halted early due to slow accrual and the COVID-19 pandemic. ORR was 18.2% (n = 4). Disease control rate was 50% (7 SD and 4 PR). Median PFS was 3.4 months (95% CI: 1.8-6.1) and median OS was 6.1 months (95% CI: 1.8-13.4). Adverse events (AE) of grade 3-4 were seen in 86% of patients, but no patients discontinued treatment due to AEs. NFE2L2 mutations were not found in responders.
Conclusions:
Although the primary endpoint was no met, sapanisertib and paclitaxel combination demonstrated clinical activity in a heavily pretreated population of mUC. This trial generates insight for future combination of sapaniserib with immunotherapy and/or antibody drug conjugates.
Insights
This Phase II trial investigated sapanisertib plus paclitaxel for metastatic urothelial carcinoma (mUC). The combination showed clinical activity, though it did not meet its primary endpoint, offering insights for future mUC therapies.
Area of Science:
- Oncology
- Pharmacology
Background:
- Metastatic urothelial carcinoma (mUC) frequently exhibits alterations in the PI3K/AKT/mTOR pathway.
- mTOR, a key protein in this cascade, is a target for novel therapies.
- Sapanisertib is a selective mTOR inhibitor investigated for its potential in mUC treatment.
Purpose of the Study:
- To evaluate the safety and efficacy of sapanisertib combined with paclitaxel in patients with mUC.
- To explore the correlation between NFE2L2 mutations and treatment response in mUC patients.
Main Methods:
- An open-label, Phase II clinical trial.
- Patients with platinum-refractory mUC received weekly paclitaxel plus oral sapanisertib.
- Objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were assessed.
Main Results:
- The study enrolled 22 patients; the trial was halted early due to slow accrual and the COVID-19 pandemic.
- The ORR was 18.2% (4/22 patients), with a disease control rate of 50%.
- Median PFS was 3.4 months and median OS was 6.1 months. Grade 3-4 adverse events occurred in 86% of patients, but no treatment discontinuations due to AEs were reported. NFE2L2 mutations were not detected in responders.
Conclusions:
- The combination of sapanisertib and paclitaxel demonstrated clinical activity in heavily pretreated mUC patients.
- While the primary endpoint was not met, the findings support further investigation of sapanisertib in combination therapies for mUC.
- Future research could explore combinations with immunotherapy or antibody-drug conjugates.
