Abstract 2591: Activity of MSC2156119J in non-small cell lung cancer models with activating EGFR mutation
Authors: Bladt Friedhelm , Friese-Hamim Manja , Blaukat Andree 
Published: August 2015

The therapeutic success of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) is hampered in a subset of patients by the development of drug resistance through the EGFR T790M ‘gate keeper’ mutation. Recent investigations suggest that aberrant activation of the c-Met receptor through c-Met amplification and/or HGF upregulation may be an additional mechanism for acquired resistance. Combination of an EGFR TKI with a c-Met inhibitor could, therefore, delay and/or prevent the emergence of c-Met-driven resistance.

The aim of our study was to evaluate the efficacy of MSC2156119J, a highly selective small molecule c-Met inhibitor, as monotherapy or in combination with EGFR TKIs (erlotinib, gefitinib and afatinib) in human xenograft models transplanted with two different primary NSCLC explants, LU342 and LU0858. While both tumors express the activated EGFR mutant form, LU342 expresses low levels of c-Met, while LU0858 expresses high levels of c-Met and carries an amplified c-Met locus.

Single-agent MSC2156119J was inactive against the low c-Met-expressing LU342 explant and tumors progressed on treatment (median tumor volume [TV] change &gt;73%). Erlotinib treatment resulted in tumor regression, with median TV change of -93% and tumor growth delay (TGD) of 56 days. The combination of MSC2156119J and erlotinib was more active, delaying tumor regrowth by 73 days compared to erlotinib monotherapy. Administration of afatinib at 5mg/kg was highly active in this model, inducing complete tumor regression (median TV change -100%), similar to the combination of afatinib and MSC2156119J.

In contrast, the LU0858 explant, which carries an amplified c-Met locus, was sensitive to MSC2156119J at a dose of 100mg/kg 5 days on and 2 days off (5 on/2 off), inducing tumor stasis with a median TV change of 19% and TGD of 34 days. While gefitinib and afatinib alone at doses of 150mg/kg 5 on/2 off and 5mg/kg 5 on/2 off, respectively, were inactive (median TV changes &gt;73%), in combination with MSC2156119J tumor growth inhibition was enhanced, resulting in tumor regression (median TV changes of -64% and -85%, respectively). In comparison, tumors treated with platinum-based doublet chemotherapy (cisplatin 5mg/kg QW/pemetrexed 200mg/kg QW) progressed, with TGD of 16 days. When MSC2156119J was combined with cisplatin/pemetrexed, antitumor activity was not significantly enhanced compared to single-agent MSC2156119J (median TV change -32%, TGD 30 days).

Together, these findings are compatible with the hypothesis that inhibition of the c-Met pathway prevents and/or delays the emergence of c-Met-driven resistance in EGFR-mutant NSCLC. Furthermore, the enhancement of antitumor activity in the low c-Met-expressing LU342 model when MSC2156119J was combined with erlotinib suggests that the combination of an EGFR TKI + MSC2156119J may also be active in tumors with low levels of c-Met expression.

Citation Format: Friedhelm Bladt, Manja Friese-Hamim, Andree Blaukat. Activity of MSC2156119J in non-small cell lung cancer models with activating EGFR mutation. [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 2591. doi:10.1158/1538-7445.AM2015-2591