Dual mTOR1/2 Inhibitor Sapanisertib (FTH-003/TAK-228) in Combination With Weekly Paclitaxel in Patients With Previously Treated Metastatic Urothelial Carcinoma: A Phase II Open-Label Study

Clin Genitourin Cancer. 2024 Oct;22(5):102123. doi: 10.1016/j.clgc.2024.102123. Epub 2024 May 23.

Abstract

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.

Keywords: Biomarkers; Chemotherapy; Pretreated; mTOR1/2 combination with immunotherapy; mTor pathway.

Publication types

  • Clinical Trial, Phase II

MeSH terms

  • Adenine / analogs & derivatives
  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols* / administration & dosage
  • Antineoplastic Combined Chemotherapy Protocols* / adverse effects
  • Antineoplastic Combined Chemotherapy Protocols* / therapeutic use
  • Benzoxazoles
  • Carcinoma, Transitional Cell / drug therapy
  • Carcinoma, Transitional Cell / genetics
  • Carcinoma, Transitional Cell / secondary
  • Drug Administration Schedule
  • Female
  • Humans
  • MTOR Inhibitors / administration & dosage
  • MTOR Inhibitors / therapeutic use
  • Male
  • Mechanistic Target of Rapamycin Complex 2 / antagonists & inhibitors
  • Middle Aged
  • Mutation
  • NF-E2-Related Factor 2 / genetics
  • NF-E2-Related Factor 2 / metabolism
  • Paclitaxel* / administration & dosage
  • Paclitaxel* / adverse effects
  • Progression-Free Survival
  • Pyrimidines / administration & dosage
  • Pyrimidines / adverse effects
  • Pyrimidines / therapeutic use
  • TOR Serine-Threonine Kinases
  • Treatment Outcome
  • Urinary Bladder Neoplasms / drug therapy
  • Urinary Bladder Neoplasms / genetics
  • Urinary Bladder Neoplasms / pathology

Substances

  • Paclitaxel
  • sapanisertib
  • Pyrimidines
  • MTOR protein, human
  • Mechanistic Target of Rapamycin Complex 2
  • NF-E2-Related Factor 2
  • NFE2L2 protein, human
  • MTOR Inhibitors
  • Adenine
  • Benzoxazoles
  • TOR Serine-Threonine Kinases