Abstract CT149: MP0250, a VEGF- and HGF-blocking multi-DARPin drug candidate, in combination with tyrosine-kinase-inhibitors targeting EGFR-mutated NSCLC: Preclinical rationale and phase Ib/II study outline

Abstract

Abstract Background: Relapse of patients with EGFR-mutated NSCLC treated with TKI regimens is most often due to TK mutation but also in a significant number of cases due to upregulation of bypass pathways, the most common being the HGF/cMET signaling pathway. Osimertinib, a third generation TKI, is currently approved for T790M-mutated NSCLC but options for treatment following relapse are unsatisfactory. Hence, there is a high medical need for therapies overcoming EGFR-TKI resistance, including inhibition of bypass mechanisms. In this respect, we are investigating combination of HGF/cMET pathway inhibition with EGFR-TKI therapy. MP0250 is a multi-DARPin drug candidate, specifically neutralizing HGF and VEGF, with the potential to block HGF-mediated bypass of EGFR-TKI inhibition in addition to exerting EGFR-independent antitumor activity via dual HGF and VEGF inhibition. We have shown that HGF expression is upregulated in most human tumors including in 4 of 5 NSCLC samples. In contrast, cMET was not highly overexpressed. MP0250 showed single-agent activity in 3 HGF-autocrine NSCLC PDX-models and an additive/synergistic effect in combination with erlotinib in an erlotinib-resistant model. These preclinical data support the reported observation that the HGF/cMET signaling pathway can confer resistance to EGFR-TKI therapy and that sensitivity to EGFR-TKIs can be restored by blocking HGF. Consequently, we have initiated a phase 1b/2 study for MP0250 in combination with osimertinib in the treatment of EGFR-mutated NSCLC patients. Trial Design: This is a phase Ib/II, single-arm, open-label, multi-center study of MP0250 in combination with osimertinib in patients with EGFR-mutated non-squamous non-small cell lung cancer (NSCLC) pretreated with osimertinib.The primary objective is to estimate the antitumor efficacy, as measured by Objective Response Rate (ORR) after 8 cycles of treatment with MP0250 i.v. every 3 weeks in combination with osimertinib orally once daily, when administered to patients with EGFR-mutated, advanced, non-squamous NSCLC after tumor progression on osimertinib and on or after the most recent therapy. Secondary and exploratory objectives are to determine safety, tolerability, progression-free survival, pharmacokinetics, immunogenicity and biomarkers. An initial dose escalation safety lead-in part, Part A, is intended to establish a safe recommended dose (RD) of MP0250 in combination with osimertinib. The cohort at RD from Part A will be expanded in order to confirm the tolerability and to further estimate the efficacy of MP0250 in combination with osimertinib. A total of 40 patients will be enrolled, 12 in part A and an additional 28 in part B at RD. Further details will be shown in the poster. Citation Format: Joachim Kiemle-Kallee, Ulrike Fiedler, Keith M. Dawson, Jutta Haunschild, Sandra Dietschy, Michael T. Stumpp, Frank Hermann, Andreas Harstrick. MP0250, a VEGF- and HGF-blocking multi-DARPin drug candidate, in combination with tyrosine-kinase-inhibitors targeting EGFR-mutated NSCLC: Preclinical rationale and phase Ib/II study outline [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 CT149.