erlotinib

Overview

First-generation reversible EGFR tyrosine kinase inhibitor.

Evidence in the corpus

  • Mutually exclusive EGFR and KRAS mutations in LUAD (n=188, P<1e-7) support independent treatment stratification: EGFR-mutant tumours (enriched in never-smokers, P=0.0046) are the primary target population for erlotinib and related EGFR TKIs. PMID:18948947
  • Prior erlotinib exposure features in the EGFR-mutant NSCLC leptomeningeal-disease (LMD) trajectories described in a 233-patient brain-metastasis cohort; LMD patients were enriched for non-canonical EGFR alterations (45% vs 21% in non-progressors, p=0.044) PMID:37591896.
  • Erlotinib was identified as a prior targeted therapy in EGFR-mutant LUAD patients who subsequently acquired BRAF fusions as a resistance mechanism (10/15 acquired-resistance cases in a 97,024-sample MSK cohort); one erlotinib + trametinib combination achieved 12 months on therapy at acquired BRAF fusion resistance PMID:38922339.
  • In preclinical HER2+ cancer cell line viability assays, erlotinib was used as EGFR TKI comparator; T-DM1 was more potent than erlotinib in HER2+ OE19 esophageal cells, consistent with the ADC delivering cytotoxic payload independently of EGFR signaling PMID:27698471.
  • Included in the CCLE pharmacogenomic screen across 947 cancer cell lines; sensitivity correlated with genomic features via elastic-net regression PMID:22460905
  • NCI-60 CellMiner analysis linked EGFR pathway activity and ABCB1 expression to erlotinib sensitivity across cancer cell lines including colon PMID:22802077
  • TCGA lung squamous study (178 tumors) examined EGFR pathway alterations relevant to erlotinib sensitivity; EGFR mutations rare in LUSC population PMID:22960745
  • Broad LUAD WES (183 tumors) confirmed EGFR-activating mutations as the primary predictor of erlotinib response; co-occurring STK11 loss associated with resistance PMID:22980975
  • Cited among ERBB-targeting agents in the list of 31 potentially actionable alterations in HCC; ERBB family alterations represent candidate targets in the HCC therapeutic landscape as of early 2014 PMID:24735922
  • Failed as a frontline HCC agent in comparison vs sorafenib: median OS 8.0–8.8 months vs 9.9–10.0 months for sorafenib (HR ~1.12–1.15) PMID:24798001
  • Matched therapy for sensitizing EGFR mutations (exon 19 del/L858R) in 860 LUAD patients via MSK-IMPACT; clinical benefit rate 84.8% in sensitizing EGFR-mutant patients; significantly lower benefit for L861Q (43%) and exon 18 deletions (40%); 1 EGFR exon 20 insertion patient treated with erlotinib had no response; 1 ERRFI1-A143D patient derived benefit despite no EGFR mutation PMID:28336552.

Resistance mechanisms

  • Non-canonical EGFR drivers (L861Q, G719A/S, A755G, N771_H773dup) persist despite TKI exposure and associate with leptomeningeal tropism PMID:37591896.

Cancer types (linked)

Sources

  • PMID:18948947 — Ding et al. 2008, Nature. Exome-scale somatic mutation landscape of 188 LUAD tumours; mutual exclusivity of EGFR and KRAS mutations supports erlotinib stratification in EGFR-mutant never-smoker LUAD.
  • PMID:37591896
  • PMID:38922339
  • PMID:27698471

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