CRIZOTINIB COMBINED WITH HSP-90 INHIBITORS

Clin Cancer Res. 2013 Dec 10. [Epub ahead of print]

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

Chen Z, Akbay EA, Mikse OR, Tupper T, Cheng K, Wang Y, Tan X, Altabef A, Woo SA, Chen L, Reibel J, Janne PA, Engelman JA, Sharpless NE, Kung AL,Shapiro GI, Wong KK.

Author information

Abstract

PURPOSE:

To extend the results of a phase III trial in non-small cell lung cancer patients with adenocarcinomas harboring EML4-ALK fusion.

EXPERIMENTAL DESIGN:

We performed 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 to chemotherapy, associated with significantly longer progression-free survival. Overall survival was also prolonged in crizotinib- compared to chemotherapy-treated mice. Pemetrexed produced superior overall survival compared to docetaxel, suggesting that this agent may be the preferred chemotherapy in the ALK population. Additionally, 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-naïve disease and support further clinical investigation of HSP90 inhibitors and second-generation ALK inhibitors in tumors with primary or acquired crizotinib resistance.