Giorgio Scagliotti1, Denis Moro-Sibilot2, Jens Kollmeier3, Adolfo Favaretto4, Eun Kyung Cho5, Heidrun Grosch6, Martin Kimmich7, Nicolas Girard8, Chun-Ming Tsai9, Te-Chun Hsia10, Matteo Brighenti11, Christian Schumann12, Xuejing Aimee Wang13, Sameera R Wijayawardana13, Aaron M Gruver13, Johan Wallin13, Kambiz Mansouri13, Volker Wacheck13, Gee-Chen Chang14. 1. Department of Oncology, Università degli Studi di Torino, Orbassano, Italy. Electronic address: giorgio.scagliotti@unito.it. 2. CHU Grenoble-Alpes, Oncologie Thoracique, Grenoble, France. 3. Lungenklinik Heckeshorn, Helios Klinikum Emil von Behring, Berlin, Germany. 4. Medical Oncology, Azienda ULSS 2 Marca Trevigiana, Treviso, Italy. 5. Gachon University Gil Hospital, Incheon, Republic of Korea. 6. Thoraxklinik Heidelberg, Heidelberg, Germany. 7. Klinik Schillerhöhe, Gerlingen, Germany. 8. Institute of Thorax Curie Montsouris, Curie Institute, Paris, France. 9. Taipei Veterans General Hospital, Taipei, Republic of China. 10. China Medical University, Taichung, Republic of China. 11. Oncology Department, Cremona Hospital Institutes, Cremona, Italy. 12. Hospital association Kempten-Oberallgäu, University Hospital Ulm, Ulm, Germany. 13. Eli Lilly and Company, Indianapolis, Indiana. 14. Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Republic of School of Medicine, National Yang-Ming University, Taipei, Republic of China.
Abstract
INTRODUCTION: The hepatocyte growth factor receptor mesenchymal-epithelial transition (MET) is reported to be a negative prognostic marker in EGFR-mutant NSCLC and involved in resistance to EGFR inhibitors. Emibetuzumab, a humanized immunoglobulin G4 monoclonal bivalent MET antibody, blocks ligand-dependent and ligand-independent hepatocyte growth factor/MET signaling. This phase 2 study compared erlotinib with and without emibetuzumab in first-line treatment of EGFR-mutant metastatic NSCLC. METHODS: Patients with stage IV EGFR-mutant NSCLC and disease control after an 8-week lead-in with erlotinib (150 mg daily) were randomized to continue taking erlotinib with or without emibetuzumab (750 mg every 2 weeks). The primary end point was progression-free survival (PFS). Additional end points included overall survival, overall response rate, safety, pharmacokinetics, and exploratory analysis of MET expression. RESULTS: No significant difference in median PFS was observed in the intent-to-treat population (9.3 months with emibetuzumab + erlotinib versus 9.5 months with erlotinib monotherapy [hazard ratio (HR) = 0.89, 90% confidence interval (CI): 0.64-1.23]). The median overall survival was 34.3 months with emibetuzumab plus erlotinib versus 25.4 months with erlotinib (HR = 0.74, 90% CI: 0.49-1.11). Emibetuzumab plus erlotinib was well tolerated, with peripheral edema and mucositis as the only adverse events occurring 10% or more frequently relative to erlotinib. Exploratory post hoc analysis showed an improvement of 15.3 months in median PFS for the 24 patients with the highest MET expression (MET expression level of 3+ in ≥90% of tumor cells) (20.7 with emibetuzumab + erlotinib versus 5.4 months with erlotinib [HR = 0.39, 90% CI: 0.17-0.91]). CONCLUSIONS: No statistically significant difference in PFS was noted in the intent-to-treat population. Exploratory analysis confirmed that high MET expression is a negative prognostic marker for patients treated with erlotinib, indicating that emibetuzumab plus erlotinib may provide clinically meaningful benefit.
INTRODUCTION: The hepatocyte growth factor receptor mesenchymal-epithelial transition (MET) is reported to be a negative prognostic marker in EGFR-mutant NSCLC and involved in resistance to EGFR inhibitors. Emibetuzumab, a humanized immunoglobulin G4 monoclonal bivalent MET antibody, blocks ligand-dependent and ligand-independent hepatocyte growth factor/MET signaling. This phase 2 study compared erlotinib with and without emibetuzumab in first-line treatment of EGFR-mutant metastatic NSCLC. METHODS: Patients with stage IV EGFR-mutant NSCLC and disease control after an 8-week lead-in with erlotinib (150 mg daily) were randomized to continue taking erlotinib with or without emibetuzumab (750 mg every 2 weeks). The primary end point was progression-free survival (PFS). Additional end points included overall survival, overall response rate, safety, pharmacokinetics, and exploratory analysis of MET expression. RESULTS: No significant difference in median PFS was observed in the intent-to-treat population (9.3 months with emibetuzumab + erlotinib versus 9.5 months with erlotinib monotherapy [hazard ratio (HR) = 0.89, 90% confidence interval (CI): 0.64-1.23]). The median overall survival was 34.3 months with emibetuzumab plus erlotinib versus 25.4 months with erlotinib (HR = 0.74, 90% CI: 0.49-1.11). Emibetuzumab plus erlotinib was well tolerated, with peripheral edema and mucositis as the only adverse events occurring 10% or more frequently relative to erlotinib. Exploratory post hoc analysis showed an improvement of 15.3 months in median PFS for the 24 patients with the highest MET expression (MET expression level of 3+ in ≥90% of tumor cells) (20.7 with emibetuzumab + erlotinib versus 5.4 months with erlotinib [HR = 0.39, 90% CI: 0.17-0.91]). CONCLUSIONS: No statistically significant difference in PFS was noted in the intent-to-treat population. Exploratory analysis confirmed that high MET expression is a negative prognostic marker for patients treated with erlotinib, indicating that emibetuzumab plus erlotinib may provide clinically meaningful benefit.
Authors: Ezra Y Rosen; Melissa L Johnson; Alexander Drilon; Geoffrey R Oxnard; Sarah E Clifford; Romel Somwar; Jennifer F Kherani; Jieun Son; Arrien A Bertram; Monika A Davare; Eric Gladstone; Elena V Ivanova; Dahlia N Henry; Elaine M Kelley; Mika Lin; Marina S D Milan; Binoj C Nair; Elizabeth A Olek; Jenna E Scanlon; Morana Vojnic; Kevin Ebata; Jaclyn F Hechtman; Bob T Li; Lynette M Sholl; Barry S Taylor; Marc Ladanyi; Pasi A Jänne; S Michael Rothenberg Journal: Clin Cancer Res Date: 2020-10-20 Impact factor: 13.801