Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance

Zhao Chen, Esra Akbay, Oliver Mikse, Tanya Tupper, Katherine Cheng, Yuchuan Wang, Xiaohong Tan, Abigail Altabef, Sue Ann Woo, Liang Chen, Jacob B. Reibel, Pasi A. Janne, Norman E. Sharpless, Jeffrey A. Engelman, Geoffrey I. Shapiro, Andrew L. Kung, Kwok Kin Wong

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1204-1211
Number of pages8
JournalClinical Cancer Research
Volume20
Issue number5
DOIs
StatePublished - 2014
Externally publishedYes

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Non-Small Cell Lung Carcinoma
Clinical Trials
Drug Therapy
docetaxel
Pemetrexed
Survival
Cytotoxins
Standard of Care
crizotinib
Disease-Free Survival
Adenocarcinoma
Research Design
Population
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance. / Chen, Zhao; Akbay, Esra; Mikse, Oliver; Tupper, Tanya; Cheng, Katherine; Wang, Yuchuan; Tan, Xiaohong; Altabef, Abigail; Woo, Sue Ann; Chen, Liang; Reibel, Jacob B.; Janne, Pasi A.; Sharpless, Norman E.; Engelman, Jeffrey A.; Shapiro, Geoffrey I.; Kung, Andrew L.; Wong, Kwok Kin.

In: Clinical Cancer Research, Vol. 20, No. 5, 2014, p. 1204-1211.

Research output: Contribution to journalArticle

Chen, Z, Akbay, E, Mikse, O, Tupper, T, Cheng, K, Wang, Y, Tan, X, Altabef, A, Woo, SA, Chen, L, Reibel, JB, Janne, PA, Sharpless, NE, Engelman, JA, Shapiro, GI, Kung, AL & Wong, KK 2014, 'Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance', Clinical Cancer Research, vol. 20, no. 5, pp. 1204-1211. https://doi.org/10.1158/1078-0432.CCR-13-1733
Chen, Zhao ; Akbay, Esra ; Mikse, Oliver ; Tupper, Tanya ; Cheng, Katherine ; Wang, Yuchuan ; Tan, Xiaohong ; Altabef, Abigail ; Woo, Sue Ann ; Chen, Liang ; Reibel, Jacob B. ; Janne, Pasi A. ; Sharpless, Norman E. ; Engelman, Jeffrey A. ; Shapiro, Geoffrey I. ; Kung, Andrew L. ; Wong, Kwok Kin. / Co-clinical trials demonstrate superiority of crizotinib to chemotherapy in ALK-rearranged non-small cell lung cancer and predict strategies to overcome resistance. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 5. pp. 1204-1211.
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abstract = "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.",
author = "Zhao Chen and Esra Akbay and Oliver Mikse and Tanya Tupper and Katherine Cheng and Yuchuan Wang and Xiaohong Tan and Abigail Altabef and Woo, {Sue Ann} and Liang Chen and Reibel, {Jacob B.} and Janne, {Pasi A.} and Sharpless, {Norman E.} and Engelman, {Jeffrey A.} and Shapiro, {Geoffrey I.} and Kung, {Andrew L.} and Wong, {Kwok Kin}",
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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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