Modeling Resistance and Recurrence Patterns of Combined Targeted-Chemoradiotherapy Predicts Benefit of Shorter Induction Period

Cancer Res. 2020 Nov 15;80(22):5121-5133. doi: 10.1158/0008-5472.CAN-19-3883. Epub 2020 Sep 9.


Optimal integration of molecularly targeted therapies, such as tyrosine kinase inhibitors (TKI), with concurrent chemotherapy and radiation (CRT) to improve outcomes in genotype-defined cancers remains a current challenge in clinical settings. Important questions regarding optimal scheduling and length of induction period for neoadjuvant use of targeted agents remain unsolved and vary among clinical trial protocols. Here, we develop and validate a biomathematical framework encompassing drug resistance and radiobiology to simulate patterns of local versus distant recurrences in a non-small cell lung cancer (NSCLC) population with mutated EGFR receiving TKIs and CRT. Our model predicted that targeted induction before CRT, an approach currently being tested in clinical trials, may render adjuvant targeted therapy less effective due to proliferation of drug-resistant cancer cells when using very long induction periods. Furthermore, simulations not only demonstrated the competing effects of drug-resistant cell expansion versus overall tumor regression as a function of induction length, but also directly estimated the probability of observing an improvement in progression-free survival at a given cohort size. We thus demonstrate that such stochastic biological simulations have the potential to quantitatively inform the design of multimodality clinical trials in genotype-defined cancers. SIGNIFICANCE: A biomathematical framework based on fundamental principles of evolution and radiobiology for in silico clinical trial design allows clinicians to optimize administration of TKIs before chemoradiotherapy in oncogene-driven NSCLC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • Carcinoma, Non-Small-Cell Lung / therapy
  • Cell Proliferation
  • Chemoradiotherapy / methods*
  • Clinical Trials as Topic
  • Disease Progression
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / genetics
  • Humans
  • Induction Chemotherapy / adverse effects
  • Induction Chemotherapy / methods*
  • Kaplan-Meier Estimate
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / genetics
  • Lung Neoplasms / therapy
  • Models, Theoretical
  • Molecular Targeted Therapy / methods
  • Neoplasm Recurrence, Local*
  • Progression-Free Survival
  • Protein Kinase Inhibitors / administration & dosage*
  • Protein Kinase Inhibitors / pharmacology
  • Radiobiology
  • Research Design
  • Time Factors


  • Protein Kinase Inhibitors
  • ErbB Receptors