2. Academic Validation
  3. Surgical window of opportunity trial reveals mechanisms of response and resistance to navtemadlin (KRT-232) in patients with recurrent glioblastoma

Surgical window of opportunity trial reveals mechanisms of response and resistance to navtemadlin (KRT-232) in patients with recurrent glioblastoma

  • medRxiv. 2024 Aug 14:2024.08.12.24311893. doi: 10.1101/2024.08.12.24311893.
Veronica Rendo,  Eudocia Q Lee,  Connor Bossi,  Nicholas Khuu,  Michelle A Rudek,  Sangita Pal,  Abigail R N Reynolds,  Auriole C R Fassinou,  Georges Ayoub,  Emily Lapinskas,  William Pisano,  John Jeang,  Sylwia A Stopka,  Michael S Regan,  Johan Spetz,  Arati Desai,  Frank Lieberman,  Joy D Fisher,  Kristine Pelton,  Raymond Y Huang,  Louis B Nabors,  Matthias Holdhoff,  Neeraja Danda,  Roy Strowd,  Serena Desideri,  Tobias Walbert,  Xiaobu Ye,  Nathalie Y R Agar,  Stuart A Grossman,  Brian M Alexander,  Patrick Y Wen,  Keith L Ligon,  Rameen Beroukhim
PMID: 39211865 DOI: 10.1101/2024.08.12.24311893
Abstract

We investigated the effectiveness of navtemadlin (KRT-232) in treating recurrent glioblastoma. A surgical window-of-opportunity trial ( NCT03107780 ) was conducted on 21 patients to determine achievable drug concentrations within tumor tissue and examine mechanisms of response and resistance. Both 120 mg and 240 mg daily dosing achieved a pharmacodynamic impact. Sequencing of three recurrent tumors revealed an absence of TP53 -inactivating mutations, indicating alternative mechanisms of resistance. In patient-derived GBM models, the lower range of clinically achieved navtemadlin concentrations induced partial tumor cell death as monotherapy. However, combining navtemadlin with temozolomide increased apoptotic rates while sparing normal bone marrow cells in vitro, which in return underwent reversible growth arrest. These results indicate that clinically achievable doses of navtemadlin generate significant pharmacodynamic effects and suggest that combined treatment with standard-of-care DNA damaging chemotherapy is a route to durable survival benefits.

Statement of significance: Tissue sampling during this clinical trial allowed us to assess mechanisms of response and resistance associated with navtemadlin treatment in recurrent GBM. We report that clinically achievable doses of navtemadlin induce pharmacodynamic effects in tumor tissue, and suggest combinations with standard-of-care chemotherapy for durable clinical benefit.

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