temozolomide

Overview

Oral alkylating agent used in CNS malignancies, including as a component of salvage regimens in relapsed/refractory CNS lymphoma and as a standard of care in glioblastoma.

Evidence in the corpus

  • Listed among prior therapies received by patients in the MSK r/r CNS lymphoma ibrutinib cohort PMID:38995739.
  • Standard treatment (temozolomide and/or radiotherapy) in IDH-mutant gliomas delays progression (PFI 40.5 vs. 27 months, P=0.009) but is associated with epigenetic evolution toward an aggressive, IDH-wildtype-like phenotype at recurrence; survival from second surgery is markedly worse in previously treated IDH-mutant patients PMID:38117484.
  • One treatment-refractory corticotroph pituitary neuroendocrine tumor (PitNET) developed acquired mismatch repair deficiency and hypermutation (93 mut/Mb) under temozolomide pressure, with 76% of mutations attributable to the alkylator signature; temozolomide was used in 77% of retrospective PitNET patients in the cohort PMID:38758238.
  • Among 35 CSF ctDNA samples from the MSK CSF series with TMB ≥13.8 mut/Mb, 2 glioma samples harbored a dominant temozolomide mutational signature, providing molecular evidence of prior TMZ exposure detectable in CSF liquid biopsy. PMID:39289779
  • Irinotecan + temozolomide was among the five matched-therapy regimens tested in the UCLA PDTO sarcoma clinical application cohort (n=5 patients); normalized organoid viability correlated with time-to-next-treatment across the matched cohort (R²=0.921, p=0.009). PMID:39305899
  • In glioblastoma (GBM), MGMT promoter methylation is a potential biomarker for response to temozolomide; however, it also serves as a prerequisite for the development of a mismatch repair-deficient hypermutator phenotype upon tumor recurrence if mismatch repair is compromised PMID:18772890.
  • MGMT promoter methylation predicts response to temozolomide + radiation specifically in the classical GBM transcriptomic subtype (p=0.01) but not in proneural, mesenchymal, or neural subtypes; 40% of the 543-patient TCGA GBM cohort received concurrent TMZ + adjuvant radiation PMID:24120142.
  • Low MGMT expression and/or MGMT VUS guided temozolomide selection in metastatic PanNEN patients PN26 and PN28 in the POG NEN WGTA cohort (n=28) PMID:24326773
  • In grade II astrocytomas, 6/10 TMZ-treated patients developed hypermutated recurrent tumors (31.9–90.9 mutations/Mb) with TMZ-signature C>T/G>A transitions; all 6 hypermutated cases progressed to GBM and acquired driver mutations in the RB and AKT–mTOR pathways PMID:24336570
  • Single-agent TMZ induction (200 mg/m² days 1–5, 28-day cycles × 6) was the induction phase in a phase II trial (NCT00588523) for newly diagnosed anaplastic oligodendroglioma (ODG3) and oligoastrocytoma (85% with 1p/19q codeletion, n=41): 70.7% completed all 6 cycles; 2-year PFS in transplanted patients was 85.7% (95% CI 62%–95.2%); in an exploratory cross-trial comparison TMZ induction was non-inferior to PCV induction (HR 3.38 for OS, P=0.005). PMID:28472509
  • Novel on-therapy mutations in melanoma patients treated with nivolumab are enriched for COSMIC signature 11 (temozolomide/melanoma signature), suggesting a stress-induced repair-process dysfunction during immunotherapy rather than prior temozolomide exposure driving these events PMID:29033130

Resistance mechanisms

  • Temozolomide can induce acquired mismatch repair deficiency and hypermutation in treated tumors; one corticotroph PitNET developed 93 mut/Mb with 76% alkylator-signature mutations under temozolomide pressure, and paradoxically became potentially susceptible to pembrolizumab PMID:38758238.
  • In IDH-mutant gliomas, temozolomide treatment is associated with epigenetic evolution toward an IDH-wildtype-like GCIMP-low phenotype at recurrence (34% vs 4% GCIMP-high-to-low transition in treated vs untreated, P=0.005), which is associated with worse post-recurrence survival PMID:38117484.
  • In glioblastoma, treatment with temozolomide can lead to a hypermutator phenotype at recurrence if MGMT promoter methylation is present and mismatch repair genes (e.g., MSH6) are compromised PMID:18772890.

Cancer types (linked)

  • PCNSL
  • ASTR
  • PTAD
  • GB
  • ODG3 — anaplastic oligodendroglioma; single-agent TMZ induction non-inferior to PCV; enables radiotherapy deferral in 1p/19q-codeleted patients.

Sources

  • PMID:38995739
  • PMID:38117484
  • PMID:38758238
  • PMID:39289779 — Hickman et al. 2024, MSK CSF ctDNA series; TMZ mutational signature detectable in glioma CSF ctDNA.
  • PMID:39305899 — Duminuco et al. 2024, UCLA PDTO sarcoma screen; irinotecan + temozolomide in matched-therapy cohort.
  • PMID:18772890 — TCGA Research Network 2008, GBM interim analysis; MGMT methylation, alkylator response, and hypermutator phenotype.
  • PMID:28472509 — Thomas et al. 2017, J Clin Oncol. Phase II NCT00588523; TMZ induction + HDC-ASCT in anaplastic oligodendroglioma; 2-year PFS 85.7% in transplanted patients; TMZ non-inferior to PCV induction.

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This page was processed by crosslinker on 2026-05-09. - PMID:24336570

This page was processed by crosslinker on 2026-05-09. - PMID:29033130

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