In clinical practice, acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC) causes EGFR TKI treatment failure. Several resistance mechanisms have been identified; EGFR T790M mutation and aberrant activation of c-Met through c-Met gene amplification and/or HGF upregulation are the two most common mechanisms. We have previously shown that combining the highly selective c-Met inhibitor tepotinib with 1st or 2nd-generation EGFR TKIs overcomes gefitinib resistance caused only by c-MET amplification. Third-generation EGFR TKIs such as rociletinib have been developed specifically to overcome T790M-mediated resistance to EGFR TKIs. We hypothesized that combining a 3rd-generation EGFR TKI with tepotinib could overcome resistance to a 1st or 2nd-generation EGFR TKI (e.g. gefitinib) regardless of the mechanism of resistance.

We assessed the efficacy of tepotinib and a Merck-synthesized version of rociletinib (MSR) as monotherapy or in combination in a NSCLC cell line xenograft model (HCC827-GR-T790M) with an EGFR del 19 mutation, c-Met amplification, and exogenous T790M expression, and in a patient-derived xenograft model (DFCI081) with an EGFR del 19 mutation and c-Met amplification, but not a T790M mutation.

Single-agent tepotinib, erlotinib, and afatinib did not show antitumor activity in HCC827-GR-T790M xenografts and tumors progressed on treatment (median tumor volume [TV] changes >73%). The combinations of tepotinib + erlotinib and tepotinib + afatinib delayed tumor regrowth more than single-agent therapy, but were no more effective than single-agent MSR. In contrast, the combination of tepotinib + MSR had strong antitumor activity in this model with double resistance due to c-Met amplification and exogenous T790M expression, resulting in complete tumor regression (median TV change -97%).

In the patient-derived xenograft model DFCI081, tumors progressed under single-agent therapy with the EGFR TKIs erlotinib, afatinib, and MSR, as expected given that this cell line expresses c-Met. In contrast, tepotinib induced complete tumor regression as monotherapy and when combined with each of the EGFR TKIs (median TV change -100%). Complete regression was maintained until the end of the 60-day observation period after treatment termination.

These findings are compatible with the hypothesis that combining tepotinib with a 3rd-generation EGFR TKI to overcome double resistance to 1st and 2nd-generation TKIs mediated by T790M and c-Met in NSCLC is more effective than using either agent alone. Furthermore, whereas EGFR TKIs were not effective in tumor models showing c-Met amplification and EGFR del 19 mutation but not T790M mutation, ie resistance is c-Met mediated, tepotinib monotherapy induced complete tumor regression.

Citation Format: Manja Friese-Hamim, Giuseppe Locatelli, Friedhelm Bladt. Combination of c-Met inhibitor tepotinib (MSC2156119J) and a third-generation EGFR inhibitor can overcome double resistance mediated by EGFR T790M mutation and c-Met amplification in non-small cell lung cancer 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 4663.