TY - JOUR
T1 - Phase 1/2 study of rilotumumab (AMG 102), a hepatocyte growth factor inhibitor, and erlotinib in patients with advanced non–small cell lung cancer
AU - Tarhini, Ahmad A.
AU - Rafique, Imran
AU - Floros, Theofanis
AU - Tran, Phu
AU - Gooding, William E.
AU - Villaruz, Liza C.
AU - Burns, Timothy F.
AU - Friedland, David M.
AU - Petro, Daniel P.
AU - Farooqui, Mariya
AU - Gomez-Garcia, Jose
AU - Gaither-Davis, Autumn
AU - Dacic, Sanja
AU - Argiris, Athanassios
AU - Socinski, Mark A.
AU - Stabile, Laura P.
AU - Siegfried, Jill M.
N1 - Publisher Copyright:
© 2017 American Cancer Society
PY - 2017/8/1
Y1 - 2017/8/1
N2 - 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.
AB - 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.
KW - amphiregulin
KW - epidermal growth factor receptor (EGFR)
KW - erlotinib
KW - hepatocyte growth factor (HGF)
KW - mesenchymal-epidermal transition factor (c-MET)
KW - neuregulin 1
KW - non–small cell lung cancer (NSCLC)
KW - rilotumumab (AMG 102)
UR - http://www.scopus.com/inward/record.url?scp=85018388214&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85018388214&partnerID=8YFLogxK
U2 - 10.1002/cncr.30717
DO - 10.1002/cncr.30717
M3 - Article
C2 - 28472537
AN - SCOPUS:85018388214
SN - 0008-543X
VL - 123
SP - 2936
EP - 2944
JO - Cancer
JF - Cancer
IS - 15
ER -