Abstract 2644: AP32788, a potent, selective inhibitor of EGFR and HER2 oncogenic mutants, including exon 20 insertions, in preclinical models

Abstract

In non-small cell lung cancer (NSCLC), multiple classes of activating mutations have been identified in EGFR and HER2 that vary widely in their sensitivity to available tyrosine kinase inhibitors (TKIs). Erlotinib, gefitinib, and afatinib are approved for use in patients with the most common forms of EGFR activating mutations (ie, exon 19 deletions or L858R substitutions). However, no TKIs are approved for patients with EGFR activated by any other mutation, including exon 20 insertions or other uncommon substitutions, or for patients with any class of HER2 activating mutation (including exon 20 insertions). As inhibition of wild-type (WT) EGFR is associated with dose-limiting toxicities, a TKI that inhibits oncogenic EGFR and HER2 variants more potently than WT EGFR is more likely to be able to be dosed to efficacious levels. AP32788 is a potent inhibitor of all oncogenic forms of EGFR and HER2, including exon 20 insertions, with selectivity over WT EGFR. Activity of AP32788 and other TKIs was assessed by measuring viability of Ba/F3 cell lines engineered to express 20 mutant variants of EGFR (n = 14) or HER2 (n = 6): 4 EGFR variants containing a common activating mutation with or without a T790M resistance mutation, 8 EGFR/HER2 variants containing an exon 20 activating insertion (eg, EGFR ASV, HER2 YVMA), and 8 EGFR/HER2 variants containing other uncommon activating mutations (eg, EGFR G719A, HER2 G776V). Inhibition of WT EGFR was assessed by measuring effects on EGFR phosphorylation in cells (A431) that over-express WT EGFR. Consistent with their clinical activity, erlotinib and gefitinib generally only inhibited the 2 EGFR variants with common activating mutations more potently than WT EGFR (IC50s 71 and 56 nM, respectively), and afatinib generally only inhibited EGFR with common activating mutations or uncommon substitutions more potently than WT EGFR (IC50 4 nM). In contrast, AP32788 inhibited all 14 mutant variants of EGFR (IC50s 2.4-22 nM), and all 6 mutant variants of HER2 (IC50s 2.4-26 nM), more potently than it inhibited WT EGFR (IC50 35 nM), including all 8 variants with exon 20 activating insertions. In mice implanted with a patient-derived tumor containing an EGFR exon 20 activating insertion, or with engineered Ba/F3 cells containing a HER2 exon 20 activating insertion, once daily oral dosing of AP32788 induced regression of tumors at doses that were well tolerated (30-100 mg/kg). In vivo efficacy was associated with inhibition of EGFR signaling in the tumor. AP32788 potently inhibited all activated forms of EGFR and HER2 tested, including exon 20 insertions, more potently than WT EGFR, suggesting it may have the selectivity necessary to achieve efficacious levels of exposure in patients. A phase 1/2 clinical trial of AP32788 in NSCLC patients is planned. Citation Format: Francois Gonzalvez, Xiaotian Zhu, Wei-Sheng Huang, Theresa E. Baker, Yaoyu Ning, Scott D. Wardwell, Sara Nadworny, Sen Zhang, Biplab Das, Yongjin Gong, Matthew T. Greenfield, Hyun G. Jang, Anna Kohlmann, Feng Li, Paul M. Taslimi, Meera Tugnait, Yongjin Xu, Emily Y. Ye, Willmen W. Youngsaye, Stephan G. Zech, Yun Zhang, Tianjun Zhou, Narayana I. Narasimhan, David C. Dalgarno, William C. Shakespeare, Victor M. Rivera. AP32788, a potent, selective inhibitor of EGFR and HER2 oncogenic mutants, including exon 20 insertions, in preclinical models. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2644.

HER2 exon 20 insertions in non-small-cell lung cancer are sensitive to the irreversible pan-HER receptor tyrosine kinase inhibitor pyrotinib

“…We initiated a multi-center phase II trial (NCT02834936) afterwards, currently in progress. Recently, it was released that poziotinib and TAK-788 (AP32788) also showed promising results in preclinical model together with early clinical setting [28,29], despite only one PR in HER2 mutation cohort in TAK-788 dose-escalation phase [30]. Jang et al [31] also reported a new HER2 Ex20Ins mutant inhibitor that was highly potent in vitro.…”

ERBB2 -Mutated Metastatic Non–Small Cell Lung Cancer: Response and Resistance to Targeted Therapies

“…Dacomitinib has shown activity in ERBB2-mutated NSCLC [24], as has neratinib [25], with more trials of this agent still ongoing alone and in combination with other agents (NCT01827267, NCT01953926, NCT02593708). Another ERBB2 TKI, AP32788, shows promise in preclinical studies involving ERBB2 exon 20 insertion mutant cancer cell lines [26], and a clinical trial is ongoing (NCT02716116). Potential activity of ado-trastuzumab emtansine is also intriguing; while our treated patient did not respond to the medication, there has been one case report showing response to the medication in a patient with ERBB2 exon 20 insertion mutation, overexpression and amplification [27].…”

OncoKB: A Precision Oncology Knowledge Base

“…Therefore, classification of loss-of-function PTEN alterations as a Level 4 alteration indicates that patients with PTEN-deficient tumors would be rational candidates for a clinical trial of investigational PI3-kinase pathway inhibitors alone or in combination with other agents, but that the use of such agents outside the context of a clinical trial is not yet supported by the sum of the clinical data. Additional examples of Level 4 alterations include NF1 inactivating alterations, which may be predictive of response to MEK1/2 inhibitors 40 , and EGFR exon 20 insertions in lung adenocarcinomas that respond poorly to erlotinib 41,42 , but which may be sensitive to AP32788, an investigational inhibitor of EGFR and HER2 43 (Fig. 3).…”