A Randomized-Controlled Phase 2 Study of the MET Antibody Emibetuzumab in Combination with Erlotinib as First-Line Treatment for EGFR Mutation–Positive NSCLC Patients

Giorgio Scagliotti, Denis Moro-Sibilot, Jens Kollmeier, Adolfo Favaretto, Eun Kyung Cho, Heidrun Grosch, Martin Kimmich, Nicolas Girard, Chun Ming Tsai, Te Chun Hsia, Matteo Brighenti, Christian Schumann, Xuejing Aimee Wang, Sameera R. Wijayawardana, Aaron M. Gruver, Johan Wallin, Kambiz Mansouri, Volker Wacheck, Gee Chen Chang

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)80-90
Number of pages11
JournalJournal of Thoracic Oncology
Volume15
Issue number1
DOIs
StatePublished - Jan 2020

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Epithelial-Mesenchymal Transition
Antibodies
Disease-Free Survival
Therapeutics
Confidence Intervals
Erlotinib Hydrochloride
Proto-Oncogene Proteins c-met
Ligands
Mucositis
Hepatocyte Growth Factor
Survival
Population
Immunoglobulins
Edema

Keywords

  • Acquired resistance
  • Antibody
  • First-line EGFR mutation
  • MET
  • NSCLC

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

A Randomized-Controlled Phase 2 Study of the MET Antibody Emibetuzumab in Combination with Erlotinib as First-Line Treatment for EGFR Mutation–Positive NSCLC Patients. / Scagliotti, Giorgio; Moro-Sibilot, Denis; Kollmeier, Jens; Favaretto, Adolfo; Cho, Eun Kyung; Grosch, Heidrun; Kimmich, Martin; Girard, Nicolas; Tsai, Chun Ming; Hsia, Te Chun; Brighenti, Matteo; Schumann, Christian; Wang, Xuejing Aimee; Wijayawardana, Sameera R.; Gruver, Aaron M.; Wallin, Johan; Mansouri, Kambiz; Wacheck, Volker; Chang, Gee Chen.

In: Journal of Thoracic Oncology, Vol. 15, No. 1, 01.2020, p. 80-90.

Research output: Contribution to journalArticle

Scagliotti, G, Moro-Sibilot, D, Kollmeier, J, Favaretto, A, Cho, EK, Grosch, H, Kimmich, M, Girard, N, Tsai, CM, Hsia, TC, Brighenti, M, Schumann, C, Wang, XA, Wijayawardana, SR, Gruver, AM, Wallin, J, Mansouri, K, Wacheck, V & Chang, GC 2020, 'A Randomized-Controlled Phase 2 Study of the MET Antibody Emibetuzumab in Combination with Erlotinib as First-Line Treatment for EGFR Mutation–Positive NSCLC Patients', Journal of Thoracic Oncology, vol. 15, no. 1, pp. 80-90. https://doi.org/10.1016/j.jtho.2019.10.003
Scagliotti, Giorgio ; Moro-Sibilot, Denis ; Kollmeier, Jens ; Favaretto, Adolfo ; Cho, Eun Kyung ; Grosch, Heidrun ; Kimmich, Martin ; Girard, Nicolas ; Tsai, Chun Ming ; Hsia, Te Chun ; Brighenti, Matteo ; Schumann, Christian ; Wang, Xuejing Aimee ; Wijayawardana, Sameera R. ; Gruver, Aaron M. ; Wallin, Johan ; Mansouri, Kambiz ; Wacheck, Volker ; Chang, Gee Chen. / A Randomized-Controlled Phase 2 Study of the MET Antibody Emibetuzumab in Combination with Erlotinib as First-Line Treatment for EGFR Mutation–Positive NSCLC Patients. In: Journal of Thoracic Oncology. 2020 ; Vol. 15, No. 1. pp. 80-90.
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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.",
keywords = "Acquired resistance, Antibody, First-line EGFR mutation, MET, NSCLC",
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TY - JOUR

T1 - A Randomized-Controlled Phase 2 Study of the MET Antibody Emibetuzumab in Combination with Erlotinib as First-Line Treatment for EGFR Mutation–Positive NSCLC Patients

AU - Scagliotti, Giorgio

AU - Moro-Sibilot, Denis

AU - Kollmeier, Jens

AU - Favaretto, Adolfo

AU - Cho, Eun Kyung

AU - Grosch, Heidrun

AU - Kimmich, Martin

AU - Girard, Nicolas

AU - Tsai, Chun Ming

AU - Hsia, Te Chun

AU - Brighenti, Matteo

AU - Schumann, Christian

AU - Wang, Xuejing Aimee

AU - Wijayawardana, Sameera R.

AU - Gruver, Aaron M.

AU - Wallin, Johan

AU - Mansouri, Kambiz

AU - Wacheck, Volker

AU - Chang, Gee Chen

PY - 2020/1

Y1 - 2020/1

N2 - 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.

AB - 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.

KW - Acquired resistance

KW - Antibody

KW - First-line EGFR mutation

KW - MET

KW - NSCLC

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