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Lapatinib with ECF/X in the first-line treatment of metastatic gastric cancer according to HER2neu and EGFR status: a randomized placebo-controlled phase II study (EORTC 40071)

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Abstract

Purpose

HER2-targeted therapy with trastuzumab and (CF/X) prolonged overall survival (OS) in metastatic HER2neu+ gastric carcinoma (GC). Lapatinib inhibits both EGFR and HER2neu. We investigated the efficacy and safety of lapatinib with epirubicin (E) + CF/X in GC according to HER2neu and EGFR status.

Methods

Tumors from chemotherapy-naïve patients were screened centrally by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). Patients with EGFR and/or HER2neu expression or amplification were allocated to three strata based on EGFR/HER2neu status and were randomized to lapatinib (arm A) or placebo (arm B), with 6 cycles of ECF or ECX (investigator-selected). The primary endpoint was progression-free survival (PFS) in stratum 3.

Results

29 of 72 screened patients were randomized to strata 1 (HER2neu+: by FISH and IHC, n = 6), 2 (HER2neu−: by FISH/+ by IHC, n = 5) and 3 (HER2neu−/EGFR+, n = 18), of which 28 patients were eligible (14 per arm). Enrollment was curtailed after announcement of the negative LOGiC trial results. Median PFS was 8.0 versus 5.9 months (HR = 0.86, 95% CI 0.37–1.99) in the per protocol population, and 8.0 versus 6.3 months (HR = 0.85, 95% CI 0.30–2.46) for stratum 3, in the lapatinib versus placebo arm respectively. Median OS was 13.8 versus 10.1 months, respectively (HR = 0.90, 95% CI 0.35–2.27). There were no safety concerns.

Conclusions

Central EGFR and HER2neu stratification by IHC and FISH can be used for further pan-HER strategies. Lapatinib with ECF/X was well tolerated, but did not show clear activity in patients with metastatic GC.

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Acknowledgements

We thank all patients who consented to enter the study. This study was undertaken by the EORTC GITCG (European Organization for Research and Treatment of Cancer Gastro-Intestinal Tract Cancer Group). The sponsor of this trial was EORTC. Trial management and data analysis were undertaken at the EORTC Headquarters (Brussels, Belgium) independently of any commercial interest.

Funding

This trial was supported by an educational grant from GlaxoSmithKline. This publication was supported by The EORTC Cancer Research Fund (ECRF) from Belgium.

Author information

Author notes

  1. Markus Moehler and Arno Schad contributed equally.

Authors and Affiliations

  1. I. Department of Internal Medicine, Johannes Gutenberg University of Mainz, Mainz, Germany

    Markus Moehler, Annett Maderer & Thomas Thomaidis

  2. Institute of Pathology, Johannes Gutenberg University of Mainz, Mainz, Germany

    Arno Schad

  3. EORTC Headquarters, Brussels, Belgium

    Ajlan Atasoy, Murielle E. Mauer, Carmela Caballero & Jestinah M. Mahachie John

  4. National Institute of Oncology, Budapest, Hungary

    Istvan Lang

  5. University Hospitals Gasthuisberg and KU Leuven, Leuven, Belgium

    Eric Van Cutsem

  6. Instituto Português de Oncologia Francisco Gentil, Lisbon, Portugal

    João Freire

  7. Department of Internal Medicine, Caritasklinikum St. Theresia, Saarbrücken, Germany

    Manfred P. Lutz

  8. Department of Oncosurgery, University of Geneva, Geneva, Switzerland

    Arnaud Roth

  9. I. Department of Internal Medicine, University Medical Center Mainz, Langenbeckstr. 1, 55131, Mainz, Germany

    Markus Moehler

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  1. Markus Moehler
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the EORTC Gastrointestinal Tract Cancer Group

Corresponding author

Correspondence to Markus Moehler.

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Ethical approval

All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Conflict of interest

Dr. Van Cutsem reports grants from Research funding from Amgen, Bayer, Boehringer, Celgene, Ipsen, Lilly, Merck, Novartis, Roche, Sanofi, outside the submitted work. All other authors have nothing to disclose.

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Moehler, M., Schad, A., Maderer, A. et al. Lapatinib with ECF/X in the first-line treatment of metastatic gastric cancer according to HER2neu and EGFR status: a randomized placebo-controlled phase II study (EORTC 40071). Cancer Chemother Pharmacol 82, 733–739 (2018). https://doi.org/10.1007/s00280-018-3667-8

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