Research Papers:
Efficacy of histology-agnostic and molecularly-driven HER2 inhibitors for refractory cancers
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Abstract
Luc Cabel1, Alina Fuerea1, Ludovic Lacroix2,3, Capucine Baldini1, Patricia Martin1, Antoine Hollebecque1,4, Sophie Postel-Vinay1, Andrea Varga1, Rastilav Balheda1, Anas Gazzah1, Jean-Marie Michot1, Aurélien Marabelle1, Etienne Rouleau2,3, Eric Solary5, Thierry De Baere6, Eric Angevin1, Jean-Pierre Armand1, Stefan Michiels7, Jean Yves Scoazec2,3, Samy Ammari8, Fabrice André4,9, Jean-Charles Soria1,9, Christophe Massard1 and Loic Verlingue1
1Drug Development Department (DITEP), Gustave Roussy Department of Medical Oncology, Faculté de Medicine Paris-Sud XI, Villejuif, France
2Laboratory of Translational Research and Biological Resource Center, AMMICA, INSERM US23/CNRS UMS3655 Department of Medical Biology and Pathology, Gustave Roussy, Villejuif, France
3Department of Medical Biology and Pathology, Gustave Roussy, Villejuif, France
4Gustave Roussy Department of Medical Oncology, Faculté de Medicine Paris-Sud XI, Villejuif, France
5Inserm Unit UMR 1170, Université Paris Saclay, Université Paris-Sud, Gustave Roussy, Villejuif, France
6Department of Interventional Radiology, Gustave Roussy, Faculté de Medicine Paris-Sud XI, Villejuif, France
7Service de Biostatistique et d'Épidémiologie, Gustave Roussy, Villejuif, France
8Department of Radiology, Gustave Roussy, Faculté de Medicine Paris-Sud XI, Villejuif, France
9Inserm Unit U981, Université Paris Saclay, Université Paris-Sud, Gustave Roussy, Villejuif, France
Correspondence to:
Christophe Massard, email: [email protected]
Keywords: ERBB2/HER2 mutation; ERBB2/HER2 amplification; targeted therapy; trastuzumab; personalized medicine
Received: November 27, 2017 Accepted: January 03, 2018 Published: January 12, 2018
ABSTRACT
A targeted therapy is recommended in case of ERBB2 alteration for breast and gastric carcinomas, but miscellaneous other tumor types are ERBB2-altered at low prevalence. Broadening the administration of HER2 inhibitors across tumor types and genomic alterations could benefit to patients with refractory metastatic tumors.
Targeted next-generation-sequencing (tNGS) and comparative genomic hybridization array (CGH) have been performed on fresh tumor biopsies of patients included in the MOSCATO-01 and ongoing MOSCATO-02 trials to administrate HER2 inhibitors in case of ERBB2 pathogenic mutation of amplification.
Between December 2011 and January 2017 a molecular analysis was performed for 934 patients (759 CGH and 912 tNGS). A novel ERBB2 alteration has been found in 4.7% (n = 44/934), including 1.5% (n = 14/912) ERBB2 mutations, and 4% (n = 30/759) ERBB2 amplifications.
A matched HER2 inhibitor was administrated to 70% (31/44) of patients and consisted in trastuzumab plus chemotherapy for 90% of them (28/31). On the 31 evaluable patients, 1 complete response (CR), 10 partial response (PR) and 2 stable disease (SD) >24 weeks were observed accounting for a clinical benefit rate (CBR) of 42% (n = 13/31, 95% CI 25–61%). Besides breast and oesogastric carcinomas, 19 patients affected by 8 different tumor types had a CBR of 25% for ERBB2 mutations (n = 2/8, 95% CI 3%–65%, with 2 PR) and 64% for ERBB2 amplifications (n = 7/11, 95% CI 31%–89%; with 1 CR, 4 PR, 2 SD).
ERBB2 genomic alterations were diffuse across metastatic tumor types and signs of efficacy emerged for HER2 targeted treatments, especially in case of ERBB2 amplifications or a p.S310Y ERBB2 mutation.
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