A window-of-opportunity trial reveals mechanisms of response and resistance to navtemadlin in patients with recurrent glioblastoma.

in Science translational medicine by Veronica Rendo, Eudocia Q Lee, Connor Bossi, Nicholas Khuu, Michelle A Rudek, Sangita Pal, Narmen Azazmeh, Rumana Rashid, Jia-Ren Lin, Margaret Cusick, Abigail R N Reynolds, Auriole C R Fassinou, Georges Ayoub, Seth Malinowski, Emily Lapinskas, William Pisano, John Jeang, Sylwia A Stopka, Michael S Regan, Johan Spetz, Arati Desai, Frank Lieberman, Kamalakannan Palanichamy, Joy D Fisher, Kristine Pelton, Raymond Y Huang, Kristopher A Sarosiek, Louis B Nabors, Matthias Holdhoff, Neeraja Danda, Roy Strowd, Serena Desideri, Tobias Walbert, Xiaobu Ye, Arnab Chakravarti, Peter K Sorger, Sandro Santagata, Nathalie Y R Agar, Stuart A Grossman, Brian M Alexander, Patrick Y Wen, Keith L Ligon, Rameen Beroukhim

TLDR

  • A surgical window-of-opportunity trial of the MDM2 inhibitor navtemadlin in 21 patients with recurrent GBM showed pharmacodynamic effects, but limited clinical benefit due to onset of resistance. Combination with temozolomide may improve outcomes, and future studies should address mechanisms of resistance and tolerance.

Abstract

Inhibitors of murine double minute homolog 2 (MDM2) represent a promising therapeutic approach for the treatment ofwild-type glioblastomas (GBMs), reactivating p53 signaling to induce cancer cell death. We conducted a surgical window-of-opportunity trial (NCT03107780) of the MDM2 inhibitor navtemadlin (KRT-232) in 21 patients withwild-type recurrent GBM to determine achievable drug concentrations within tumor tissues and biological mechanisms of response and resistance. Participants received navtemadlin at 120 mg (= 10) or 240 mg (= 11) for 2 days before surgical resection and after surgery until progression or unacceptable toxicity. Both 120 and 240 mg daily dosing achieved a pharmacodynamic impact, but median progression-free survival was 3.1 months. DNA sequencing of three recurrent tumors revealed an absence of-inactivating mutations, indicating alternative mechanisms of resistance. To understand the mechanisms of response and resistance associated with navtemadlin, we conducted functional and spatial analyses of human tissue and patient-derived GBM neurosphere models. Navtemadlin induced partial tumor cell death as monotherapy, and combination with temozolomide enhanced apoptosis in GBM neurospheres while sparing normal bone marrow cells in vitro. We also observed up-regulation of oligodendrocyte differentiation genes with navtemadlin treatment and enrichment of oligodendrocyte transcription factor 2 (OLIG2)-positive cells at relapse, suggesting an unexplored mechanism of navtemadlin tolerance in GBM. Overall, these results indicated that clinically achievable doses of navtemadlin exert pharmacodynamic effects on GBM and suggest that combined treatment with temozolomide may be a route to more durable survival benefits.

Overview

  • The study aimed to investigate the therapeutic potential of the MDM2 inhibitor navtemadlin (KRT-232) in treating wild-type glioblastomas (GBMs).
  • The study involved a surgical window-of-opportunity trial of navtemadlin in 21 patients with recurrent GBM, with the goal of determining achievable drug concentrations within tumor tissues and biological mechanisms of response and resistance.
  • The study aimed to identify pharmacodynamic effects of navtemadlin, as well as potential mechanisms of resistance and tolerance, to inform future treatment strategies.

Comparative Analysis & Findings

  • Both 120 and 240 mg daily dosing of navtemadlin achieved pharmacodynamic impact, but median progression-free survival was only 3.1 months.
  • DNA sequencing of three recurrent tumors revealed no inactivating mutations, indicating alternative mechanisms of resistance to navtemadlin.
  • Functional and spatial analyses of human tissue and patient-derived GBM neurosphere models showed that navtemadlin induced partial tumor cell death as monotherapy, and that combination with temozolomide enhanced apoptosis in GBM neurospheres while sparing normal bone marrow cells.

Implications and Future Directions

  • The study suggests that clinically achievable doses of navtemadlin can exert pharmacodynamic effects on GBM, and that combining navtemadlin with temozolomide may be a route to more durable survival benefits.
  • Future studies should aim to identify and address alternative mechanisms of resistance to navtemadlin, as well as explore the potential mechanism of navtemadlin tolerance in GBM.
  • The finding that navtemadlin up-regulates oligodendrocyte differentiation genes and enriches OLIG2-positive cells at relapse suggests a potential role for navtemadlin in promoting oligodendrocyte-mediated tumor tolerance.
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