Abstract 4698: Combination of ceritinib (LDK378) with PI3K inhibitors (buparlisib [BKM120] and alpelisib [BYL719]) demonstrates synergistic preclinical antitumor activity in ALK-rearranged non-small cell lung cancer (NSCLC)

Abstract

Abstract Introduction: NSCLCs harboring rearrangements of the anaplastic lymphoma kinase (ALK) gene are highly sensitive to ALK inhibition. Ceritinib is a novel ALK inhibitor that demonstrates significant preclinical and clinical antitumor potency, including in tumors that have developed resistance to the approved ALK inhibitor crizotinib. Upregulation of the phosphatidylinositol 3-kinase (PI3K) pathway may be involved in ALK inhibitor resistance, suggesting that combining ceritinib with a PI3K inhibitor may provide synergistic antitumor activity in ALK-rearranged NSCLC. Here, we assess the synergy and antiproliferative activity of PI3K inhibitor/ceritinib combinations in crizotinib-naïve primary preclinical models of NSCLC. Methods: In vitro experiments used the EML4−ALK-translocated lung cancer cell line H2228 to screen for synergistic combinations of ceritinib with 18 other compounds (PI3K, MEK, and CDK4/6 inhibitors, among others). In vivo experiments used a human-mouse primary xenograft lung cancer model with similar EML4−ALK translocation (LUF1656). Tumor fragments (diameter 2−3 mm) from stock mice inoculated with LUF1656 lung cancer tissue were harvested and used for inoculation into nu/nu mice for tumor development. Once mean tumor size had reached ∼150 mm3, treatment was initiated with single-agent or combination regimens of buparlisib (pan-PI3K inhibitor; 35 mg/kg QD), alpelisib (PI3Kα inhibitor; 30 mg/kg QD), or ceritinib (25 mg/kg [low dose] or 50 mg/kg [full dose] QD). All doses used were equivalent to known therapeutic doses in patients. Results: In vitro experiments revealed the strongest antiproliferative activity when ceritinib was combined with either buparlisib or alpelisib versus the other compounds tested. In vivo, low-dose ceritinib in combination with buparlisib improved tumor growth delay over single-agent, full-dose ceritinib. Full-dose ceritinib plus alpelisib showed no significant difference in tumor growth delay versus full-dose ceritinib alone. Low-dose ceritinib plus alpelisib appeared to be better tolerated than full-dose ceritinib plus alpelisib, but with similar efficacy to low-dose ceritinib alone. A delayed tumor growth rate after treatment interruption was noted in all ceritinib combinations. Conclusion: Synergy was observed between ceritinib and PI3K inhibitors in a crizotinib-naïve ALK-translocated lung model in vitro. In the in vivo EML4−ALK lung preclinical cancer models, low-dose ceritinib (25 mg/kg) combined with buparlisib showed improved efficacy versus full-dose ceritinib (50 mg/kg) alone. Preclinical experiments exploring combinations of PI3K- and ALK-targeted therapies in crizotinib-resistant ALK-rearranged tumors are also ongoing. Citation Format: Emmanuelle Di Tomaso, Ronald Linnartz, Fang Li, Cristian Massacesi, Samit Hirawat. Combination of ceritinib (LDK378) with PI3K inhibitors (buparlisib [BKM120] and alpelisib [BYL719]) demonstrates synergistic preclinical antitumor activity in ALK-rearranged non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4698. doi:10.1158/1538-7445.AM2015-4698