BACKGROUND: Activation of the mesenchymal-epidermal transition factor (MET) 
tyrosine kinase and its ligand, hepatocyte growth factor (HGF), is implicated in 
resistance to epidermal growth factor receptor (EGFR) inhibitors. In this phase 
1/2 trial, rilotumumab (an anti-HGF antibody) combined with erlotinib was 
evaluated in patients with metastatic, previously treated non-small cell lung 
cancer.
METHODS: In phase 1, a dose de-escalation design was adopted with rilotumumab 
starting at 15 mg/kg intravenously every 3 weeks and oral erlotinib 150 mg 
daily. In phase 2, the disease control rate (DCR) (according to Response 
Evaluation Criteria in Solid Tumors) of the combination was evaluated using a 
Simon 2-stage design. The biomarkers examined included 10 plasma-circulating 
molecules associated with the EGFR and MET pathways.
RESULTS: Without indications for de-escalation, the recommended phase 2 dose was 
dose level 0. Overall, 45 response-evaluable patients were enrolled (13 with 
squamous carcinoma, 32 with adenocarcinoma; 2 had confirmed EGFR mutations, 33 
had confirmed wild-type [WT] EGFR, and 7 had KRAS mutations). The DCR for all 
patients was 60% (90% confidence interval [CI], 47.1%-71.3%). Median 
progression-free survival was 2.6 months (90% CI, 1.4-2.7 months), and median 
overall survival was 6.6 months (90% CI, 5.6-8.9 months). Among patients with WT 
EGFR, the DCR was 60.6% (90% CI, 46.3%-73.3%), median progression-free survival 
was 2.6 months (90% CI, 1.4-2.7 months), and median overall survival was 7.0 
months (90% CI, 5.6-13.4 months). Elevated baseline levels of neuregulin 1 were 
associated with longer progression-free survival (hazard ratio, 0.41; 95% CI, 
0.19-0.87), whereas elevated amphiregulin levels were associated with more rapid 
progression (hazard ratio, 2.14; 95% CI, 1.48-3.08).
CONCLUSIONS: Combined rilotumumab and erlotinib had an acceptable safety 
profile, and the DCR met the prespecified criteria for success. In the EGFR WT 
group, the DCR exceeded published reports for erlotinib alone. High circulating 
levels of neuregulin 1 may indicate sensitivity to this combination. Cancer 
2017;123:2936-44. © 2017 American Cancer Society.