Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: Implications for clinical trial design Journal Article


Authors: Chaft, J. E.; Oxnard, G. R.; Sima, C. S.; Kris, M. G.; Miller, V. A.; Riely, G. J.
Article Title: Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: Implications for clinical trial design
Abstract: Purpose: Treatment of patients with oncogene-addicted cancers with tyrosine kinase inhibitors (TKI) is biologically and clinically different than with cytotoxic chemotherapy. We have observed that some patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib (RECIST progression after initial benefit) have accelerated progression of disease after discontinuation of TKI. To examine this observation and define the course of patients following TKI discontinuation, we systematically evaluated patients enrolled on clinical trials of agents to treat acquired resistance to erlotinib or gefitinib. Methods: We evaluated patients with EGFR-mutant lung cancer who participated in trials for patients with acquired resistance that mandated TKI discontinuation before administration of study therapy. Disease flare was defined as hospitalization or death attributable to disease progression during the washout period. Results: Fourteen of 61 patients (23%; 95% CI: 14-35) experienced a disease flare. The median time to disease flare after TKI discontinuation was 8 days (range 3-21). Factors associated with disease flare included shorter time to progression on initial TKI (P = 0.002) and the presence of pleural (P = 0.03) or CNS disease (P = 0.01). There was no association between disease flare and the presence of T790M at the time of acquired resistance. Conclusions: In patients with EGFR-mutant lung cancer and acquired resistance to epidermal growth factor receptor TKIs, discontinuation of erlotinib or gefitinib before initiation of study treatment is associated with a clinically significant risk of accelerated disease progression. Clinical trials in this patient population must minimize protocol-mandated washout periods. ©2011 AACR.
Keywords: adult; clinical article; controlled study; aged; middle aged; exon; gene deletion; mutation; clinical trial; disease course; erlotinib; drug withdrawal; antineoplastic agents; bone metastasis; lung neoplasms; epidermal growth factor receptor; lung cancer; bone pain; receptor, epidermal growth factor; drug resistance, neoplasm; risk factor; cancer mortality; time factors; protein tyrosine kinase inhibitor; dyspnea; protein kinase inhibitors; hypoxia; liver failure; liver metastasis; hospitalization; disease progression; gefitinib; brain metastasis; pleura effusion; seizure; point mutation; quinazolines; peritoneum metastasis; disease exacerbation; meningeal metastasis; heart tamponade; pleura metastasis; central nervous system disease; pleura disease; heart metastasis; withholding treatment
Journal Title: Clinical Cancer Research
Volume: 17
Issue: 19
ISSN: 1078-0432
Publisher: American Association for Cancer Research  
Date Published: 2011-10-01
Start Page: 6298
End Page: 6303
Language: English
DOI: 10.1158/1078-0432.ccr-11-1468
PROVIDER: scopus
PUBMED: 21856766
PMCID: PMC3756539
DOI/URL:
Notes: --- - "Export Date: 2 November 2011" - "CODEN: CCREF" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Camelia S Sima
    204 Sima
  2. Vincent Miller
    261 Miller
  3. Jamie Erin Chaft
    126 Chaft
  4. Gregory J Riely
    344 Riely
  5. Geoffrey R Oxnard
    24 Oxnard
  6. Mark Kris
    597 Kris