Tumor mutation burden and efficacy of EGFR-tyrosine kinase inhibitors in patients with EGFR-mutant lung cancers Journal Article

Authors: Offin, M.; Rizvi, H.; Tenet, M.; Ni, A.; Sanchez-Vega, F.; Li, B. T.; Drilon, A.; Kris, M. G.; Rudin, C. M.; Schultz, N.; Arcila, M. E.; Ladanyi, M.; Riely, G. J.; Yu, H.; Hellmann, M. D.
Article Title: Tumor mutation burden and efficacy of EGFR-tyrosine kinase inhibitors in patients with EGFR-mutant lung cancers
Abstract: Purpose: Tumor mutation burden (TMB) is a biomarker of response to immune checkpoint blockade (ICB). The impact of TMB on outcomes with targeted therapies has not been explored. Experimental Design: We identified all patients with metastatic EGFR exon19del or L858R-mutant lung cancers treated with first/second-generation EGFR tyrosine kinase inhibitors (TKIs) with pretreatment next-generation sequencing data (MSK-IMPACT assay). The effect of TMB on time-to-treatment discontinuation (TTD) and overall survival (OS) were evaluated in univariate and multivariate analyses. EGFR wild-type lung adenocarcinoma samples were used for comparison. Results: Among 153 patients with EGFR-mutant lung cancer, TMB was lower compared with EGFR wildtype (n = 1,849; median 3.77 vs. 6.12 mutations/Mb; P < 0.0001) with a broad range (0.82-17.9 mutations/Mb). Patients with EGFR-mutant lung cancer whose tumors had TMB in the high tertile had shorter TTD (HR, 0.46; P = 0.0008) and OS (HR, 0.40; P = 0.006) compared with patients with low/intermediate TMB. Evaluating by median TMB, there was significantly shorter TTD and OS for patients with higher TMB (TTD, P = 0.006; OS, P = 0.03). In multivariate analysis, TTD and OS remained significantly longer in the low/intermediate tertile compared with high TMB (HR = 0.57, P = 0.01; HR = 0.50, P = 0.02, respectively). In paired pretreatment and postprogression samples, TMB was increased at resistance (median 3.42 vs. 6.56 mutations/Mb; P = 0.008). Conclusions: TMB is negatively associated with clinical outcomes in metastatic patients with EGFR-mutant lung cancer treated with EGFR-TKI. This relationship contrasts with that seen in lung cancers treated with immunotherapy.
Keywords: paclitaxel; adenocarcinoma; carboplatin; gefitinib; ctla-4 blockade; sensitivity; landscape; factor-receptor gene; osimertinib; neoantigens
Journal Title: Clinical Cancer Research
Volume: 25
Issue: 3
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2019-02-01
Start Page: 1063
End Page: 1069
Language: English
ACCESSION: WOS:000457395900020
DOI: 10.1158/1078-0432.Ccr-18-1102
PMCID: PMC6347551
PUBMED: 30045933
Notes: Source: Wos
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MSK Authors
  1. Helena Alexandra Yu
    89 Yu
  2. Marc Ladanyi
    870 Ladanyi
  3. Gregory J Riely
    346 Riely
  4. Maria Eugenia Arcila
    343 Arcila
  5. Mark Kris
    602 Kris
  6. Alexander Edward Drilon
    141 Drilon
  7. Matthew David Hellmann
    168 Hellmann
  8. Nikolaus D Schultz
    202 Schultz
  9. Charles Rudin
    162 Rudin
  10. Bob Tingkan Li
    59 Li
  11. Ai   Ni
    48 Ni
  12. Hira Abbas Rizvi
    20 Rizvi
  13. Michael David Offin
    15 Offin
  14. Megan Alexandra Tenet
    3 Tenet