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Efficacy of osimertinib plus bevacizumab in glioblastoma patients with simultaneous EGFR amplification and EGFRvIII mutation

  • Clinical Study
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Abstract

Background

Amplification of EGFR and its active mutant EGFRvIII are common in glioblastoma (GB). While EGFR and EGFRvIII play critical roles in pathogenesis, targeted therapy with EGFR-tyrosine kinase inhibitors or antibodies has shown limited efficacy. To improve the likelihood of effectiveness, we targeted adult patients with recurrent GB enriched for simultaneous EGFR amplification and EGFRvIII mutation, with osimertinib/bevacizumab at doses described for non-small cell lung cancer.

Methods

We retrospectively explored whether previously described EGFRvIII mutation in association with EGFR gene amplification could predict response to osimertinib/bevacizumab combination in a subset of 15 patients treated at recurrence. The resistance pattern in a subgroup of subjects is described using a commercial next-generation sequencing panel in liquid biopsy.

Results

There were ten males (66.7%), and the median patient’s age was 56 years (range 38–70 years). After their initial diagnosis, 12 patients underwent partial (26.7%) or total resection (53.3%). Subsequently, all cases received IMRT and concurrent and adjuvant temozolomide (TMZ; the median number of cycles 9, range 6–12). The median follow-up after recurrence was 17.1 months (95% CI 12.3–22.6). All patients received osimertinib/bevacizumab as a second-line intervention with a median progression-free survival (PFS) of 5.1 months (95% CI 2.8–7.3) and overall survival of 9.0 months (95% CI 3.9–14.0). The PFS6 was 46.7%, and the overall response rate was 13.3%. After exposure to the osimertinib/bevacizumab combination, the main secondary alterations were MET amplification, STAT3, IGF1R, PTEN, and PDGFR.

Conclusions

While the osimertinib/bevacizumab combination was marginally effective in most GB patients with simultaneous EGFR amplification plus EGFRvIII mutation, a subgroup experienced a long-lasting meaningful benefit. The findings of this brief cohort justify the continuation of the research in a clinical trial. The pattern of resistance after exposure to osimertinib/bevacizumab includes known mechanisms in the regulation of EGFR, findings that contribute to the understanding and targeting in a stepwise rational this pathway.

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Data availability

The datasets presented in this article are not readily available because of the Colombian organic law of data protection that limits access to genetic information in an open format. Requests to access the datasets should be directed to the corresponding author, who will release it upon formal request to the Ministry of Health of Colombia following the requirements of Law 1581 of 2012, paragraph 201811601170851 of 2018.

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Acknowledgements

The authors are grateful for the generous contribution from the Silberman family and Francisco Castillo (Fundación Neuronas con Corazón) for altruistically promoting the development of brain tumor research in Colombia.

Funding

Supported by Foundation for Clinical and Applied Cancer Research—FICMAC (Bogotá, Colombia) research Grant 014-2018.

Author information

Author notes

  1. Andrés F. Cardona, Daniel Jaramillo-Velásquez and Alejandro Ruiz-Patiño contributed equally to the study.

Authors and Affiliations

  1. Clinical and Translational Oncology Group, Brain Tumor Unit, Clínica del Country, Calle 116 No. 9 – 72, c. 318, Bogotá, Colombia

    Andrés F. Cardona & Leonardo Rojas

  2. Foundation for Clinical and Applied Cancer Research – FICMAC, Bogotá, Colombia

    Andrés F. Cardona, Alejandro Ruiz-Patiño, Carolina Polo, Camila Ordoñez, July Rodríguez, Jenny Avila, Elvira Jaller, Carolina Sotelo & Nicolas Santoyo

  3. Molecular Oncology and Biology Systems Research Group (Fox-G), Universidad El Bosque, Bogotá, Colombia

    Andrés F. Cardona, Alejandro Ruiz-Patiño, Carolina Polo, Camila Ordoñez, July Rodríguez, Jenny Avila, Leonardo Rojas, Elvira Jaller, Carolina Sotelo & Nicolas Santoyo

  4. Neurosurgery Department, Fundación Santa Fe de Bogotá, Bogotá, Colombia

    Daniel Jaramillo-Velásquez, Enrique Jiménez, Fernando Hakim, Diego Gómez, Juan Fernando Ramón, Juan Armando Mejía & Fernando Salguero

  5. Neurosurgery Department, Clínica del Country, Bogotá, Colombia

    Hernando Cifuentes

  6. Radio-Oncology Department, Fundación Santa Fe de Bogotá, Bogotá, Colombia

    Álvaro Muñoz

  7. Neuroradiology Section, Radiology Department, Fundación Santa Fe de Bogotá, Bogotá, Colombia

    Sonia Bermúdez & Nicolas Useche

  8. Neuroradiology Section, Radiology Department, Clínica del Country, Bogotá, Colombia

    Diego Pineda

  9. Pathology Department, Mayo Clinic, Rochester, MN, USA

    Luisa Ricaurte

  10. Laboratory of Personalized Medicine, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico

    Zyanya Lucia Zatarain-Barrón & Oscar Arrieta

  11. Clinical Oncology Department, Clínica Colsanitas, Bogotá, Colombia

    Leonardo Rojas

  12. Division of Hematology/Oncology, Mayo Clinic, Scottsdale, USA

    Juan Esteban Garcia-Robledo

  13. Center for Thoracic Oncology, Tisch Cáncer Center, Mount Sinai Hospital System & Icahn School of Medicine, Mount Sinai, New York, NY, USA

    Christian Rolfo

  14. Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Barcelona, Spain

    Rafael Rosell

  15. Thoracic Oncology Unit, Clínica del Country, Bogotá, Colombia

    Andrés F. Cardona

Authors
  1. Andrés F. Cardona
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  2. Daniel Jaramillo-Velásquez
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  28. Oscar Arrieta
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Contributions

AFC, OA, ARP, EJ, FH, DG, JFR, HC and JAM planned and coordinated the study. DJV, CP, FS, CO, AM, SB, NU, DP, LR, ZLZ, EJ and CS reviewed patient records and composed the database. LR reviewed all histopathology studies. JR, JA, JGR, NS and ARP performed DNA extraction and library preparation and MGMT methylation analysis. AFC, ARP, OA, CR, and RR performed all statistical analysis and data interpretation. AFC, ARP, OA and DJV wrote the initial draft of the manuscript. All authors contributed to the article and approved the submitted version.

Corresponding author

Correspondence to Andrés F. Cardona.

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Conflict of interest

Andrés F. Cardona discloses financial research support from Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Foundation Medicine, Roche Diagnostics, Termo Fisher, Broad Institute, Amgen, Flatiron Health, Teva Pharma, Rochem Biocare, Bayer, INQBox and The Foundation for Clinical and Applied Cancer Research—FICMAC. Additionally, he was linked and received honoraria as an advisor, participate in speakers' bureau. He gave expert testimony to EISAI, Merck Serono, Jannsen Pharmaceutical, Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Pfizer, Novartis, Celldex Therapeutics, Foundation Medicine, Eli Lilly, Guardant Health, Illumina, and Foundation for Clinical and Applied Cancer Research—FICMAC. Oscar Arrieta reports personal fees from Pfizer, grants and individual fees from Astra Zeneca, grants and individual fees from Boehringer-Ingelheim, Lilly, Merck, Bristol Myers Squibb, Roche, outside the submitted work. Christian Rolfo reports relation with Mylan, Archer Biosciences, Oncopass, Inivata, Merck Serono Novartis, MSD, Boehringer Ingelheim, Guardant Health, etc. AstraZeneca as part of Speakers' Bureau. Also, he received research funding from Pfizer and had uncompensated Relationships with OncoDNA, Biomark, and Guardant Health. Leonardo Rojas received honoraria as an advisor, participate in speakers’ bureau from Merck Sharp & Dohme, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Astra Zeneca and Eli Lilly. Additionally, he was linked and received honoraria as researcher. All other authors have no conflicts to declare.

Ethical approval

This study was reviewed and approved by ONCOLGroup Platform—Registration No. 2018/21904, Cayre, Clínica del Country, Bogotá, Colombia. All included patients provided signed informed consent and accepted the tumor tissue analysis. An Institutional Review Board and Privacy Board waiver was obtained to facilitate retrospective collection of clinical, pathologic and molecular data.

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Cardona, A.F., Jaramillo-Velásquez, D., Ruiz-Patiño, A. et al. Efficacy of osimertinib plus bevacizumab in glioblastoma patients with simultaneous EGFR amplification and EGFRvIII mutation. J Neurooncol 154, 353–364 (2021). https://doi.org/10.1007/s11060-021-03834-3

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  • DOI: https://doi.org/10.1007/s11060-021-03834-3

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