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This open-label Phase II study conducted prior to routine EGFR mutation testing, assessed whether acquired resistance to erlotinib in NSCLC patients with a given MET protein expression level enriched for EGFRmt could be overcome by emibetuzumab, an antibody against MET. Although some responses were seen, the trial did not meet its primary endpoint. Introduction: The hepatocyte growth factor receptor MET represents a resistance mechanism to epidermal growth factor receptor (EGFR) inhibition in EGFR mutant (mt) non-small cell lung cancer (NSCLC). This Phase 2 study tested whether acquired resistance to erlotinib in MET protein positive NSCLC patients enriched for EGFRmt can be overcome by emibetuzumab plus erlotinib. Patient and Methods: Patients with Stage IV NSCLC with acquired resistance to erlotinib and MET diagnostic (+) (>= 10% of cells expressing MET at >= 2+ IHC staining intensity at any time) were randomized (3:1) to receive emibetuzumab 750 mg every 2 weeks with or without erlotinib 150 mg once daily. The primary objective was to evaluate the overall response rate (ORR) relative to historic control, with a co-primary objective of ORR in patients with MET expression in >= 60% of cells >= 2+ (MET > 60%). Results: One hundred and eleven MET+ patients received emibetuzumab plus erlotinib (N = 83) or emibetuzumab monotherapy (N = 28). 89 of 111 MET+ samples were post-erlotinib. ORR was 3.0% for emibetuzumab plus erlotinib (95% CI: 0.4, 10.5) and 4.3% for emibetuzumab (95% CI: 0.1, 21.9), in patients with post-erlotinib progression biopsies available (n = 89). Similar results were observed in patients with MET >= 60% expression (n = 74). Disease control rate and progression-free survival were higher for emibetuzumab plus erlotinib (50%/3.3 months) than for emibetuzumab (26%/1.6 months). No unexpected safety signals emerged. Partial responses were observed in patients with and without EGFRmt or MET amplification. EGFR sensitizing mutations were identified retrospectively in 84.2% of those with available tissue (85/101). Conclusion: Acquired resistance to erlotinib in MET diagnostic (+) patients was not reversed by emibetuzumab plus erlotinib or emibetuzumab monotherapy, although a subset of patients obtained clinical benefit. (C) 2022 Elsevier Inc. All rights reserved.

Summary Purpose Approximately 3% of lung cancer bears mutations leading to MET exon 14 skipping, an oncogenic driver which is further evidenced by case reports of patient response to MET kinase inhibitor treatment. Approximately 15% of tumors harboring MET exon14 skipping have concurrent MET amplification. Experimental Design Merestinib is a type II MET kinase inhibitor. Emibetuzumab, a bivalent anti-MET antibody, internalizes MET receptor. Each single agent and the combination were evaluated in the Hs746t gastric cancer line bearing MET exon14 skipping and MET amplification. Results Merestinib inhibited Hs746t cell proliferation (IC50=34 nM) and totally eliminated pMET at 100nM. Emibetuzumab showed little anti-proliferative activity against Hs746t cells (IC50>100nM), did not reduce pMET, and slightly reduced cell surface MET. In the Hs746t xenograft model, dose dependent differences in durability of response were seen with merestinib including durable tumor regression (91.8%) at 12 mg/kg qd. Emibetuzumab treatment (10mg/kg qw) provided transient tumor regression (37.7%), but tumors re-grew while on treatment. Concurrent combination of merestinib (6 mg/kg qd) and emibetuzumab resulted in 85% tumor regression, while a sequential combination (initiating merestinib first) resulted in longer duration of treatment response. Conclusions Data in this study support a clinical evaluation of merestinib in patients with MET exon 14 skipping (NCT02920996). As a type II MET kinase inhibitor, merestinib may provide a therapeutic option to treatment naïve patients or to patients who progress on type I MET inhibitor treatment. Data also support clinical evaluation of the sequential combination of merestinib with emibetuzumab when patients progress on single agent merestinib.

9019 Background: MET expression is a mechanism of resistance to EGFR inhibition in EGFRmt NSCLC and correlated with poor prognosis. Emi (LY2875358) is a humanized IgG4 monoclonal bivalent MET antibody that blocks ligand dependent and independent HGF/MET signaling. This Phase 2 study compared the clinical activity of Emi + E versus single agent E in 1st line EGFRmt metastatic NSCLC. Methods: Stage IV, EGFRmt NSCLC pts with disease control following an 8-week lead-in E (150 mg PO QD) treatment were randomized 1:1 to receive Emi (750 mg IV Q2W) + E or E alone. Pts were stratified by ECOG PS, ethnicity, MET expression status, and response at the end of the lead-in. The primary endpoint was PFS from randomization. Additional endpoints included safety, OS, PK, and exploratory analysis of MET-expressing populations. Results: Out of181 pts enrolled, 141 pts were randomized (Emi+E: 71; E: 70). In the ITT population, median PFS for EMI+E was 9.3 months (m) compared with 9.5 m for E (HR = 0.89: 90% CI 0.64-1.23; p = 0.534). Exploratory analysis of MET-high expressing pts (MET 3+ expression in ≥90% of tumor cells; n = 24 pts) showed a 15.3 m improvement in PFS (EMI+E: 20.7 m; E: 5.4 m [HR: 0.39; 90% CI: 0.17-0.91]). No difference in PFS was observed in the complementary population (HR: 1.1 [90% CI: 0.7-1.7]). Similar frequencies of related AEs were reported for both treatment arms. Drug-related TEAEs that were more frequent ( > 10%) for Emi+E were peripheral edema and fatigue (all grade 1 or 2). Emi serum concentrations were consistent with previously obtained PK results, and no apparent exposure-response was observed. Median OS in the ITT population was not achieved (NA) for either arm. In MET-high expressing pts, median OS was 20.6 m for E (90% CI: 8.87, NA) whereas it was not achieved for Emi+E (90% CI: NA, NA). Conclusions: No statistically significant difference in PFS was noted in the ITT population.Exploratory analysis confirmed that high MET expression is a negative prognostic marker for pts treated with E and indicated that these pts may receive clinically meaningful benefit from Emi+E. Clinical trial information: NCT01897480.

9070Background: MET signaling represents one mechanism of resistance to EGFR inhibition in EGFR mutant (mt) NSCLC. Emibetuzumab (LY2875358, LY) is a humanized IgG4 monoclonal bivalent MET antibody ...

300 Background: The mesenchymal-epithelial transition factor (MET) pathway is upregulated by anti-vascular endothelial growth factor (VEGF) therapies in vivo. Emibetuzumab (E) is a bivalent monoclonal anti-MET antibody that inhibits ligand-dependent and ligand-independent MET signaling. Here we report safety and initial anti-tumor activity for the combination of E plus ramucirumab (R), a human VEGFR-2 antibody in patients (pts) with advanced hepatocellular cancer (HCC) as part of a Phase 1b/2 study (NCT02082210). Methods: Pts with Child Pugh A advanced or metastatic HCC and no further standard therapy available received E (750 mg flat dose) and R (8mg/kg) intravenously every 2 weeks (Q2W) on a 28 day cycle. The primary objective was to evaluate safety and tolerability of the E+R dose and schedule in this patient population. As a co-primary objective, preliminary antitumor activity by RECIST v1.1 was studied. Exploratory objectives included evaluation of biomarkers for MET/HGF and VEGF pathways from fresh pre-treatment tumor biopsies. Results: As of July 2015, 15 pts were treated with E + R in the HCC expansion cohort. Most of the pts had ECOG PS of < 2, and prior sorafenib therapy. Ten pts (67%) experienced ≥ 1 drug-related adverse events (AEs). Commonly related AEs included fatigue (33%), peripheral edema (33%), hypertension (27%), and hypophosphatemia (27%). Most of these events were mild or moderate in severity and the only ≥ grade 3 related events reported included 1 case each of grade 3 fatigue, hypertension, neutropenia, leukopenia, and lymphopenia. In the 9 pts evaluable for response, there were 2 partial responses (PR; 1 unconfirmed, pt still ongoing) and 5 additional pts had stable disease for a disease control rate of 47% (7/15). Six pts were not evaluable and 5 pts remained on treatment at the time of data cut-off. Five pts received 4 or more cycles of therapy, including 1 pt ongoing in cycle 10. Both patients with PR were positive for MET expression. Updated results will be presented at the meeting. Conclusions: The combination of 750 mg E plus 8mg/kg R at Q2W demonstrated an acceptable safety profile and early evidence of antitumor activity in pts with advanced HCC. Clinical trial information: NCT02082210.