Abstract 4806: Exploring optimal targeted combination therapies with neratinib for HER2 mutated NSCLC
Authors: Kuraguchi Mari , Taus Luke J. , Zhou Shan , Avogadri-Connors Francesca , Cutler Richard E. , Lalani Alshad S. , Kirschmeier Paul , Jänne Pasi A. 
Published: August 2018

Abstract
Genetic alterations which constitutively activate human epidermal growth factor receptor 2 (HER2; ERBB2) without overexpression have been observed in patients with non-small cell lung cancer (NSCLC) yet currently there are no effective targeted therapies for such patients. Neratinib is an orally available, quinazoline-based, irreversible pan-HER tyrosine kinase inhibitor. Prior clinical studies have demonstrated that neratinib alone or in combination with temsirolimus has low response rates in patients with HER2 mutated NSCLC. Since dual HER2-tageting is showing promising activity in breast cancer, we hypothesized that combination of neratinib with other HER2-targeted agents, such as trastuzumab and ado-trastuzumab emtansine (T-DM1), may provide better anti-tumor efficacy compared to neratinib alone. To address this, we have developed, under an IRB approved protocol, two NSCLC patient-derived xenograft (PDX) models bearing HER2 kinase domain mutations, DFCI-315 (ERBB2 P780_Y781insGSP) and DFCI-359 (ERBB2 755_757LREdelinsPR). These PDX lines were characterized by different tumor kinetics and doubling times of approximately 12 and 52 days, respectively. IHC analysis confirmed the expression, but not overexpression, of HER2 with H-scores of 70.0 and 54.2, respectively. Treatment with single agent neratinib (P.O. QD x 28 days, 40 mg/kg) was effective in both HER2 mutant lung models, leading to a significant tumor growth inhibition (TGI) with tumor stasis in DFCI-315 (p&lt;0.0001) and tumor regression (TR) of &gt;20% in DFCI-359 (p&lt;0.05). DFCI-315 was insensitive to monotherapy with trastuzumab (I.P. 2x/week x 4 weeks, 20 mg/kg) but responded to monotherapy with T-DM1 (I.V. QWK x 4 weeks, 3 mg/kg) resulting in about 50% TGI (p&lt;0.005). Both agents in combination with neratinib showed additional anti-tumor activity leading to TR in the DFCI-315 model (p&lt;0.0001 vs vehicle), though difference from neratinib alone was not significant. In contrast, DFCI-359 model responded dramatically to neratinib plus trastuzumab combination starting from Day 5 of dosing, reaching TR of 62% by 3 weeks, compared to 25-30% TR by either of single agents (p&lt;0.0001 vs vehicle, p&lt;0.05 vs neratinib or trastuzumab). Tumor growth stasis following the combination treatment was durable for at least 10 days after the drug withdrawal, while the tumors regrew immediately after the drug withdrawal following neratinib treatment alone. Surprisingly, T-DM1 had no anti-tumor activity in this model and its combination with neratinib was indifferent from neratinib alone. Taken together, these data demonstrate neratinib has efficacy as single agent in preclinical models of HER2 mutant NSCLC and its anti-tumor activity was enhanced when combined with trastuzumab. Neratinib plus trastuzumab is a promising combination treatment for HER2 mutant lung cancer and is currently under clinical investigation (ClinicalTrials.gov NCT01953926).
Citation Format: Mari Kuraguchi, Luke J. Taus, Shan Zhou, Francesca Avogadri-Connors, Richard E. Cutler, Alshad S. Lalani, Paul Kirschmeier, Pasi A. Jänne. Exploring optimal targeted combination therapies with neratinib for HER2 mutated NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4806.