TY - JOUR
T1 - Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance
AU - Chen, Zhao
AU - Akbay, Esra
AU - Mikse, Oliver
AU - Tupper, Tanya
AU - Cheng, Katherine
AU - Wang, Yuchuan
AU - Tan, Xiaohong
AU - Altabef, Abigail
AU - Woo, Sue Ann
AU - Chen, Liang
AU - Reibel, Jacob B.
AU - Janne, Pasi A.
AU - Sharpless, Norman E.
AU - Engelman, Jeffrey A.
AU - Shapiro, Geoffrey I.
AU - Kung, Andrew L.
AU - Wong, Kwok Kin
PY - 2014
Y1 - 2014
N2 - Purpose: To extend the results of a phase III trial in patients with non-small cell lung cancer with adenocarcinomas harboring EML4-ALK fusion. Experimental Design: We conducted a co-clinical trial in a mouse model comparing the ALK inhibitor crizotinib to the standard-of-care cytotoxic agents docetaxel or pemetrexed. Results: Concordant with the clinical outcome in humans, crizotinib produced a substantially higher response rate compared with chemotherapy, associated with significantly longer progression-free survival. Overall survival was also prolonged in crizotinib- compared with chemotherapy-treated mice. Pemetrexed produced superior overall survival compared with docetaxel, suggesting that this agent may be the preferred chemotherapy in the ALK population. In addition, in the EML4-ALK-driven mouse lung adenocarcinoma model, HSP90 inhibition can overcome both primary and acquired crizotinib resistance. Furthermore, HSP90 inhibition, as well as the second-generation ALK inhibitor TAE684, demonstrated activity in newly developed lung adenocarcinoma models driven by crizotinib-insensitive EML4-ALK L1196M or F1174L. Conclusions: Our findings suggest that crizotinib is superior to standard chemotherapy in ALK inhibitor-naive disease and support further clinical investigation of HSP90 inhibitors and secondgeneration ALK inhibitors in tumors with primary or acquired crizotinib resistance.
AB - Purpose: To extend the results of a phase III trial in patients with non-small cell lung cancer with adenocarcinomas harboring EML4-ALK fusion. Experimental Design: We conducted a co-clinical trial in a mouse model comparing the ALK inhibitor crizotinib to the standard-of-care cytotoxic agents docetaxel or pemetrexed. Results: Concordant with the clinical outcome in humans, crizotinib produced a substantially higher response rate compared with chemotherapy, associated with significantly longer progression-free survival. Overall survival was also prolonged in crizotinib- compared with chemotherapy-treated mice. Pemetrexed produced superior overall survival compared with docetaxel, suggesting that this agent may be the preferred chemotherapy in the ALK population. In addition, in the EML4-ALK-driven mouse lung adenocarcinoma model, HSP90 inhibition can overcome both primary and acquired crizotinib resistance. Furthermore, HSP90 inhibition, as well as the second-generation ALK inhibitor TAE684, demonstrated activity in newly developed lung adenocarcinoma models driven by crizotinib-insensitive EML4-ALK L1196M or F1174L. Conclusions: Our findings suggest that crizotinib is superior to standard chemotherapy in ALK inhibitor-naive disease and support further clinical investigation of HSP90 inhibitors and secondgeneration ALK inhibitors in tumors with primary or acquired crizotinib resistance.
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U2 - 10.1158/1078-0432.CCR-13-1733
DO - 10.1158/1078-0432.CCR-13-1733
M3 - Article
C2 - 24327273
AN - SCOPUS:84895817152
SN - 1078-0432
VL - 20
SP - 1204
EP - 1211
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 5
ER -