Abstract LB-360: Afatinib prolonged survival in EGFR-driven lung cancer model compared to gefitinib
Authors: Ninomiya Takashi , Ichihara Eiki , Hisamoto Akiko , Hotta Katsuyuki , Tanimoto Mitsune , Kiura Katsuyuki , Takigawa Nagio , Ochi Nobuaki , Yasugi Masayuki , Harada Daijiro 
Published: August 2012

Afatinib (BIBW2992) is an irreversible pan-HER inhibitor. Kinase inhibitors have different dissociation constant for binding deletion mutation and point mutation in EGFR. We previously reported that afatinib with short-term (4 weeks) administration tended to be more effective for treatment of lung cancer model induced by the deletion mutation in exon 19 than gefitinib, although similar effect of both drugs was observed in L858R mutated mice (#3566, AACR 2011). Our present study was carried out to investigate the preclinical efficacy of long-term treatment of afatinib in lung cancer harboring deletion mutation in EGFR exon 19. We generated transgenic mice expressing the delE748-A752 mutant of mouse EGFR, which is equivalent to the delE746-A750 mutant, driven by the SP-C promoter (Cancer Sci 99, 2008). The mice invariably developed multi-focal lung adenocarcinomas of various sizes at 5 weeks of age and died of lung cancer, if left untreated. To evaluate the efficacy of afatinib on survival in the mice, afatinib, gefitinib (5 mg/kg/day, n=15 each) or vehicle alone (n=13) was administered orally from 7 weeks of age until inability to take due to toxicity or death. All mice in the control group died and the median survival time (MST) was 17 weeks. At the time, 12 gefitinib-treated mice and 6 afatinib-treated mice died, and the afatinib-treated mice survived longer significantly than gefitinib-treated mice (MST: not reached vs 54 weeks; p &lt; 0.05 by logrank test). No toxic death was observed in all mice. After the initiation of treatment at week 4, the body weight of the mice in the control group was significantly lower than that in gefitinib or afatinib group. The gefitinib-treated mice significantly lost weight compared to afatinib-treated mice after 34 weeks. To understand the efficacy of afatinib in the mice, EGFR/HER2 protein expression was determined by immunoblotting assay. The mice of 14 weeks of age were sacrificed at 2, 6, 10, 14, and 18 hours after single administration of each drug. In gefitinib-treated mice, phosphorylated EGFR (pEGFR) was suppressed at 2 and 6 hours but was recovered at 10 hours. On the other hand, in afatinib-treated mice, pEGFR was suppressed at 2, 6, and 10 hours and was partially recovered at 14 and 18 hours. At 14 hours, the expressions of pEGFR in gefitinib-treated mice and in afatinib-treated mice were more and less than those in mice without treatment, respectively. In gefitinib-treated mice, phosphorylated HER2 (pHER2) was recovered at 10 hours after decreasing at 2 and 6 hours. Presumably, EGFR/HER2 heterodimer might be suppressed temporally by gefitinib. In afatinib-treated mice, pHER2 was suppressed from 2 to 18 hours. The results suggest that afatinib is more effective than gefitinib because it suppresses pEGFR for longer time than gefitinib. In conclusion, our data suggest that afatinib can well control lung cancer driven by EGFR exon19 deletion mutation longer than gefitinib.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-360. doi:1538-7445.AM2012-LB-360