osimertinib

Overview

Third-generation EGFR tyrosine kinase inhibitor active against T790M and sensitizing mutations, with CNS penetration.

Evidence in the corpus

  • Non-canonical EGFR mutations in NSCLC brain metastases may identify patients at elevated risk for leptomeningeal disease and partial resistance to osimertinib, with persistence across serial tissue/CSF samples despite maximal EGFR-directed and local therapy PMID:37591896.
  • BRAF fusions represent a recurrent (2–4%) mechanism of acquired resistance to osimertinib in EGFR-mutant LUAD; median time from EGFR TKI start to acquired BRAF fusion detection was 23 months (range 9–37) across 15 patients PMID:38922339.
  • One vignette showed emergence then clearance of EGFR T790M under osimertinib while ongoing L861Q/G719S drivers persisted PMID:37591896.
  • LMD patients had more EGFR alterations than non-progressors (45% vs 21%, p=0.044) PMID:37591896.
  • In MSK-CHORD (n=29 NSCLC on immunotherapy with PDL1 testing), EGFR T790M and concomitant MET amplifications were enriched after prior targeted therapy (including osimertinib) in EGFR-mutant NSCLC. The survival advantage seen in EGFR-mutant LUAD was attributed to receipt of targeted therapy rather than EGFR mutation status itself. PMID:39506116
  • SETD2-mutant LUAD patients on immunotherapy showed longer time-to-next-treatment-or-death (HR 0.5, 95% CI 0.36–0.72) but not after targeted therapy (HR 0.8, 95% CI 0.58–1.15), suggesting SETD2 is a biomarker for immunotherapy rather than osimertinib/targeted-therapy benefit in LUAD. PMID:39506116
  • Third-generation EGFR TKI used in FLAURA and AURA3 trials; review reports consistent outcomes across age subgroups in young-onset NSCLC (YLC); only 1/63 Indian YLC patients on TKIs received osimertinib (1.5%) due to access disparities PMID:27346245
  • Cited as preferred agent for atypical EGFR alleles (L861Q, exon 18 del) alongside afatinib and dacomitinib based on allele-specific response data from 860-patient MSK-IMPACT LUAD cohort; EGFR T790M present in 5.5% (47/860) of cases, all post-EGFR-TKI, identifying a population for osimertinib PMID:28336552.

Resistance mechanisms

  • Non-canonical EGFR drivers (L861Q, G719A/S, A755G, N771_H773dup) persist under osimertinib and associate with leptomeningeal tropism PMID:37591896.
  • T790M can emerge and then clear under osimertinib while uncommon primary drivers remain PMID:37591896.

Cancer types (linked)

Sources

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