Inhibition of the Phosphatidylinositol-3 Kinase Pathway Using Bimiralisib in Loss-of-Function NOTCH1-Mutant Head and Neck Cancer

Faye M. Johnson, Filip Janku, Mohamed A. Gouda, Hai T. Tran, Jitesh D. Kawedia, Debora Schmitz, Hendrik Streefkerk, J. Jack Lee, Clark R. Andersen, Defeng Deng, Seema Rawal, Pooja A. Shah, Adel K. El-Naggar, Jason M. Johnson, Mitchell J. Frederick

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Background: PI3K/mTOR inhibition leads to apoptosis of NOTCH1-mutant head and neck squamous cell carcinoma (HNSCC) cells. We tested the efficacy of the PI3K/mTOR inhibitor bimiralisib in patients with NOTCH1-mutant HNSCC. Methods: Patients with recurrent/metastatic NOTCH1-mutant HNSCC who had progressed during chemotherapy and immunotherapy received bimiralisib until unacceptable toxicity or progression. To assess whether NOTCH1 mutations can be detected in blood, we measured circulating tumor DNA (ctDNA). To assess activated NOTCH1 protein levels, we quantitated cleaved NOTCH1 (cl-NOTCH) by immunohistochemistry. Results: Eight patients were treated, and 6 were evaluable for response. The objective response rate was 17%. For all 8 patients, median progression-free and overall survival was 5 and 7 months, respectively. Bimiralisib was well tolerated, with expected hyperglycemia. Pharmacokinetic values were consistent with published studies. NOTCH1 mutations were detected in 83.3% of ctDNA. Staining for tumor cl-NOTCH1 was negative. The trial closed early due to sponsor insolvency. Conclusion: Although the trial was small, outcomes with bimiralisib were better than the historical standard of care; Results will need to be confirmed in a larger trial. The lack of cl-NOTCH1 was consistent with loss-of-function mutations and validated our mutation function algorithm. The ability to detect NOTCH1 mutations in blood will help future studies. (ClinicalTrials.gov Identifier: NCT03740100).

Original languageEnglish
Pages (from-to)1004-1005 AND E919-E926
JournalOncologist
Volume27
Issue number12
DOIs
StatePublished - 9 Dec 2022
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2022 The Author(s). Published by Oxford University Press.

Keywords

  • NOTCH1
  • PI3 kinase
  • head and neck squamous cell carcinoma
  • mTOR
  • pharmacokinetics

Fingerprint

Dive into the research topics of 'Inhibition of the Phosphatidylinositol-3 Kinase Pathway Using Bimiralisib in Loss-of-Function NOTCH1-Mutant Head and Neck Cancer'. Together they form a unique fingerprint.

Cite this