Andrés F Cardona1,2,3,4, Daniel Jaramillo-Velásquez5, Alejandro Ruiz-Patiño6,7, Carolina Polo6,7, Enrique Jiménez5, Fernando Hakim5, Diego Gómez5, Juan Fernando Ramón5, Hernando Cifuentes8, Juan Armando Mejía5, Fernando Salguero5, Camila Ordoñez6,7, Álvaro Muñoz9, Sonia Bermúdez10, Nicolas Useche10, Diego Pineda11, Luisa Ricaurte12, Zyanya Lucia Zatarain-Barrón13, July Rodríguez6,7, Jenny Avila6,7, Leonardo Rojas14,7,15, Elvira Jaller6,7, Carolina Sotelo6,7, Juan Esteban Garcia-Robledo16, Nicolas Santoyo6,7, Christian Rolfo17, Rafael Rosell18, Oscar Arrieta13. 1. Clinical and Translational Oncology Group, Brain Tumor Unit, Clínica del Country, Calle 116 No. 9 - 72, c. 318, Bogotá, Colombia. andres.cardona@clinicadelcountry.com. 2. Foundation for Clinical and Applied Cancer Research - FICMAC, Bogotá, Colombia. andres.cardona@clinicadelcountry.com. 3. Molecular Oncology and Biology Systems Research Group (Fox-G), Universidad El Bosque, Bogotá, Colombia. andres.cardona@clinicadelcountry.com. 4. Thoracic Oncology Unit, Clínica del Country, Bogotá, Colombia. andres.cardona@clinicadelcountry.com. 5. Neurosurgery Department, Fundación Santa Fe de Bogotá, Bogotá, Colombia. 6. Foundation for Clinical and Applied Cancer Research - FICMAC, Bogotá, Colombia. 7. Molecular Oncology and Biology Systems Research Group (Fox-G), Universidad El Bosque, Bogotá, Colombia. 8. Neurosurgery Department, Clínica del Country, Bogotá, Colombia. 9. Radio-Oncology Department, Fundación Santa Fe de Bogotá, Bogotá, Colombia. 10. Neuroradiology Section, Radiology Department, Fundación Santa Fe de Bogotá, Bogotá, Colombia. 11. Neuroradiology Section, Radiology Department, Clínica del Country, Bogotá, Colombia. 12. Pathology Department, Mayo Clinic, Rochester, MN, USA. 13. Laboratory of Personalized Medicine, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico. 14. Clinical and Translational Oncology Group, Brain Tumor Unit, Clínica del Country, Calle 116 No. 9 - 72, c. 318, Bogotá, Colombia. 15. Clinical Oncology Department, Clínica Colsanitas, Bogotá, Colombia. 16. Division of Hematology/Oncology, Mayo Clinic, Scottsdale, USA. 17. Center for Thoracic Oncology, Tisch Cáncer Center, Mount Sinai Hospital System & Icahn School of Medicine, Mount Sinai, New York, NY, USA. 18. Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Barcelona, Spain.
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.
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.
Authors: C Mircea S Tesileanu; Linda Dirven; Maarten M J Wijnenga; Johan A F Koekkoek; Arnaud J P E Vincent; Hendrikus J Dubbink; Peggy N Atmodimedjo; Johan M Kros; Sjoerd G van Duinen; Marion Smits; Martin J B Taphoorn; Pim J French; Martin J van den Bent Journal: Neuro Oncol Date: 2020-04-15 Impact factor: 12.300
Authors: Daniel J Brat; Kenneth Aldape; Howard Colman; Dominique Figrarella-Branger; Gregory N Fuller; Caterina Giannini; Eric C Holland; Robert B Jenkins; Bette Kleinschmidt-DeMasters; Takashi Komori; Johan M Kros; David N Louis; Catriona McLean; Arie Perry; Guido Reifenberger; Chitra Sarkar; Roger Stupp; Martin J van den Bent; Andreas von Deimling; Michael Weller Journal: Acta Neuropathol Date: 2020-01-29 Impact factor: 17.088
Authors: Daniel J Brat; Kenneth Aldape; Howard Colman; Eric C Holland; David N Louis; Robert B Jenkins; B K Kleinschmidt-DeMasters; Arie Perry; Guido Reifenberger; Roger Stupp; Andreas von Deimling; Michael Weller Journal: Acta Neuropathol Date: 2018-09-26 Impact factor: 17.088
Authors: Felix Sahm; Daniel Schrimpf; David T W Jones; Jochen Meyer; Annekathrin Kratz; David Reuss; David Capper; Christian Koelsche; Andrey Korshunov; Benedikt Wiestler; Ivo Buchhalter; Till Milde; Florian Selt; Dominik Sturm; Marcel Kool; Manuela Hummel; Melanie Bewerunge-Hudler; Christian Mawrin; Ulrich Schüller; Christine Jungk; Antje Wick; Olaf Witt; Michael Platten; Christel Herold-Mende; Andreas Unterberg; Stefan M Pfister; Wolfgang Wick; Andreas von Deimling Journal: Acta Neuropathol Date: 2015-12-15 Impact factor: 17.088
Authors: Michael Weller; Martin van den Bent; Matthias Preusser; Emilie Le Rhun; Jörg C Tonn; Giuseppe Minniti; Martin Bendszus; Carmen Balana; Olivier Chinot; Linda Dirven; Pim French; Monika E Hegi; Asgeir S Jakola; Michael Platten; Patrick Roth; Roberta Rudà; Susan Short; Marion Smits; Martin J B Taphoorn; Andreas von Deimling; Manfred Westphal; Riccardo Soffietti; Guido Reifenberger; Wolfgang Wick Journal: Nat Rev Clin Oncol Date: 2020-12-08 Impact factor: 66.675
Authors: David N Louis; Arie Perry; Pieter Wesseling; Daniel J Brat; Ian A Cree; Dominique Figarella-Branger; Cynthia Hawkins; H K Ng; Stefan M Pfister; Guido Reifenberger; Riccardo Soffietti; Andreas von Deimling; David W Ellison Journal: Neuro Oncol Date: 2021-08-02 Impact factor: 13.029