64IN - Secondary resistance to systemic treatment

Date 29 September 2014
Event ESMO 2014
Session The evolving role of systemic treatment in advanced NSCLC
Topics Drug Development
Non-Small-Cell Lung Cancer, Metastatic
Translational Research
Presenter Egbert Smit
Citation Annals of Oncology (2014) 25 (suppl_4): iv23-iv23. 10.1093/annonc/mdu304
Authors E.F. Smit1, A.C. Dingemans2
  • 1Pulmonary Diseases, VUMC, 1007 MB - Amsterdam/NL
  • 2Pulmonology, Maastricht University Medical Center (MUMC), 6202 AZ - Maastricht/NL




The majority of molecular selected patients treated with targeted agents will eventually relapse due to incomplete target suppression, second site mutations and activation of alternative kinases to maintain signal flux to downstream effectors. Clinical strategies to overcome secondary resistance Patients with oligo-progressive disease can efficiently be treated with local therapy (radiotherapy, surgery) while TKI-treatment continues. Switching to chemotherapy or withhold TKI's for a period of time followed by re-initiation (EGFR holiday) is common practice. The combination of afatinib with cetuximab, showed evident clinical activity in EGFR TKi resistant patients. Promising phase I trial results of two new agents, CO-1686, and AZ-9291, both selectively targeting EGFR mutations, were recently presented. Alk rearranged patients progressing on treatment with crizotinib have been found to exhibit major and long lasting responses to the second generation ALK inhibitors Ceritinib, AP26113 and Alectinib. Importantly, there is evidence that at least one of these agents, Ceritinib, has activity against tumors that have ALK TK mutations conferring resistance to Crizotinib. Similar to clinical strategies to overcome EGFR TKI resistance, retreatment after a crizotinib holiday has been reported to induce clinical response in a case report.


With the introduction of targeted treatments, it became clear that tumor characteristics are dynamic and may alter during the course of targeted treatment. Some secondary resistance mechanisms are amendable to further treatment.


All authors have declared no conflicts of interest.