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Original Article|Articles in Press

RET-MAP: An international multi-center study on clinicobiologic features and treatment response in patients with lung cancer harboring a RET fusion

Open AccessPublished:January 13, 2023DOI:https://doi.org/10.1016/j.jtho.2022.12.018
RET-MAP: An international multi-center study on clinicobiologic features and treatment response in patients with lung cancer harboring a RET fusion
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      ABSTRACT

      Introduction

      Nearly 1-2% of non-small cell lung cancers (NSCLC) harbor RET fusions. Characterization of this rare population is still incomplete.

      Methods

      This retrospective multi-center study included patients with any-stage RET+ NSCLC from 31 cancer centers. Molecular profiling included DNA/RNA sequencing and/or FISH analyses. Clinico-biological features and treatment outcomes (per investigator) with surgery, chemotherapy, immune-checkpoint blockers (ICB), chemotherapy-ICB, multi-tyrosine kinase inhibitors (MTKi) and RET inhibitors (RETi) were evaluated.

      Results

      For 218 patients included between February 2012 and April 2022, median age was 63 years, 56% were females, 93% had adenocarcinoma, and 41% were smokers. The most frequent fusion partner was KIF5B (72%). Median tumor mutational burden (TMB) was 2.5 [range, 1-4] mut/Mb and median PD-L1 expression was 10% [range, 0-55]. The most common metastatic sites were lung (50%), bone (43%) and pleura (40%). Central nervous system metastases were found at diagnosis of advanced NSCLC in 21% of patients and at last follow-up or death in 31%. Overall response rate and median progression-free survival were 55% and 8.7 months with platinum doublet, 26% and 3.6 months with single-agent chemotherapy, 46% and 9.6 months with chemotherapy-ICB, 23% and 3.1 months with ICB, 37% and 3 months with MTKi, and 76% and 16.2 months with RETi, respectively. Median overall survival was longer in patients treated with RETi versus no RETi (50.6 months [37.7-72.1] versus 16.3 months [12.7-28.8], P<0.0001).

      Conclusions

      Patients with RET+ NSCLC have mainly thoracic and bone disease, and low TMB and PD-L1 expression. RETi significantly improve survival, while ICB may be active in selected patients.

      Keywords

      Article info

      Publication history

      Accepted: December 22, 2022
      Received in revised form: November 5, 2022
      Received: May 24, 2022

      Publication stage

      In Press Journal Pre-Proof

      Footnotes

      Funding:

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Disclosure Statement of Conflict of Interest

      Mihaela Aldea ([email protected]) – Expenses: Sandoz; Advisory Board: Viatris; Research funding: Sandoz.

      Arianna Marinello ([email protected]) – no disclosures.

      Michael Duruisseaux ([email protected]) - Membership of an advisory council or committee for BMS, GSK, Sanofi, MSD, AstraZeneca, Abbvie, Takeda, Boehringer Ingelheim, Merus, Amgen, Guardant and Pfizer; consulting fees from Roche, BMS, MSD, AstraZeneca, Abbvie, Takeda, Boehringer Ingelheim, Gamamabs Pharma and Pfizer; research grants from Takeda, NanoString, Lilly and Blueprint.

      Wael Zrafi ([email protected]) – no disclosures.

      Nicole Conci ([email protected]) - no disclosures.

      Giacomo Massa ([email protected]) – no disclosures.

      Giulio Metro ([email protected]) – no disclosures.

      Isabelle Monnet ([email protected]) – no disclosures.

      Patricia Iranzo Gomez ([email protected]) – no disclosures.

      Fabrizio Tabbo ([email protected]) – no disclosures.

      Emilio Bria ([email protected]) - is supported by Institutional funds of Università Cattolica del Sacro Cuore (UCSC-projects D1) and by the Fondazione Associazione Italiana per la Ricerca sul Cancro (AIRC) with Investigator Grant (IG) No. IG20583. E.B. received advisory and speakers’ fee from MSD, Astra-Zeneca, Celgene, Pfizer, Helsinn, Eli-Lilly, BMS, Novartis, and Roche.

      Florian Guisier ([email protected]) – no disclosures.

      Damien Vasseur ([email protected]) – no disclosures.

      Colin R. Lindsay ([email protected]) – has received personal fees from Amgen for lectures/workshops and is a consultant/advisor for Amgen and CBPartners. He has received institutional research funding from Amgen, Apollomics, Boehringer Ingelheim, Mirati Therapeutics, Revolution Medicines, and Roche for his work as a Chief/Principal Investigator on clinical trials.

      Santiago Ponce ([email protected]) - Consulting, advisory role or lectures from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Roche, Amgen.

      Sophie Cousin ([email protected]) – no disclosures.

      Fabrizio Citarella ([email protected]) - no disclosures.

      Vincent Fallet ([email protected]) - personal fees from MSD, Novartis, Roche, Sanofi and Boehringer; personal fees and non-financial support from Astra Zeneca, BMS, Takeda, Jansen and Pfizer, all outside the submitted work.no disclosures.

      Jose Nicolas Minatta ([email protected]) - Research Grants: Pfizer. Consulting/Advisory Board/ Educational: MSD, Pfizer, Takeda, Roche, Merck, Amgen.

      Anna Eisert ([email protected]) – Honoraria: Amgen, Merck.

      Hortense de Saint Basile ([email protected]) – no disclosures.

      Clarisse Audigier-Valette ([email protected]) - no disclosures.

      Laura Mezquita ([email protected]) - research grant/Funding (self) from Bristol Myers Squibb, Boehringer Ingelheim, Amgen, Stilla, Inivata; advisory/consultancy from Roche, Takeda; honoraria (self) from Bristol Myers Squibb, Roche, Takeda, AstraZeneca; travel/Accommodation/Expenses from Roche, Bristol Myers Squibb, Takeda, AstraZeneca; non-remunerated activity/ies from AstraZeneca.

      Antonio Calles ([email protected]) - Honoraria: AstraZeneca, Boehringer-Ingelheim, Bayer, Pfizer, Roche, Novartis, Merck Sharp & Dohme, and Bristol Myers Squibb; Consulting or advisory role: AstraZeneca, Boehringer-Ingelheim, Pfizer, Roche/Genentech, Eli Lilly and Company, Novartis, Takeda, Merck Sharp & Dohme, and Bristol Myers Squibb; Research funding: Merck Sharp & Dome; Travel financial support: Roche, Boehringer-Ingelheim, Merck Sharp & Dohme, and Bristol Myers Squibb; Stock Ownership: None

      Giannis Mountzios ([email protected]) – Advisory and consultation fees: AstraZeneca, BMS, MSD, Roche, Takeda, Novartis, AMGEN, Pfizer, Takeda, GSK, Sanofi; Travel and accommodation fees: AstraZeneca, BMS, MSD, Roche, Takeda, Novartis, GSK, Sanofi; PI in sponsored clinical trials: Novartis, Roche, MSD, AstraZeneca, Merck, ΒΜS, AMGEN, Ιmmunomedics, GSK, Sanofi

      Marco Tagliamento ([email protected]) - travel grants from Roche, Bristol-Myers Squibb, AstraZeneca, Takeda, Eli Lilly and Honoraria as medical writer from Novartis, Amgen, Merck Sharp & Dohme.

      Jordi Remon Masip ([email protected]) - Travel, accommodation, congress registration expenses from Ose-Immunotherapeutic ; advisory and consultation fees : BMS, MSD, Janssen, Takeda.

      Judith Raimbourg ([email protected]) – no disclosures.

      Safae Terrisse ([email protected]) – no disclosures.

      Alexandro Russo ([email protected]) - no disclosures.

      Diego Cortinovis ([email protected]) - no disclosures.

      Philippe Rochigneux ([email protected]) – Speaker/ board: Novartis, Astra Zeneca, Viatris. Travel expenses: Pfizer.

      David James Pinato ([email protected]) - DJP received lecture fees from ViiV Healthcare, Bayer Healthcare, BMS, Roche, EISAI, Falk Foundation, travel expenses from BMS and Bayer Healthcare; consulting fees for Mina Therapeutics, EISAI, Roche, DaVolterra and Astra Zeneca; research funding (to institution) from MSD and BMS.

      Alessio Cortellini ([email protected]) – AC received consulting fees from MSD, BMS, AstraZeneca, Roche; speakers’ fee from AstraZeneca, MSD, Novartis and Astellas.

      Camille Leonce ([email protected]) - no disclosures.

      Anas Gazzah ([email protected]) - Travel, accommodation, congress registration expenses from Boehringer Ingelheim, Novartis, Pfizer, Roche; Consultant/Expert role for Novartis; Principal/sub-Investigator of Clinical Trials for Aduro Biotech, Agios Pharmaceuticals, Amgen, Argen-X Bvba, Arno Therapeutics, Astex Pharmaceuticals, Astra Zeneca, Aveo, Bayer Healthcare Ag, Bbb Technologies Bv, Beigene, Bioalliance Pharma, Biontech Ag, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Ca, Celgene Corporation, Chugai Pharmaceutical Co., Clovis Oncology, Daiichi Sankyo, Debiopharm S.A., Eisai, Exelixis, Forma, Gamamabs, Genentech, Inc., Gilead Sciences, Inc, Glaxosmithkline, Glenmark Pharmaceuticals, H3 Biomedicine, Inc, Hoffmann La Roche Ag, Incyte Corporation, Innate Pharma, Iris Servier, Janssen , Kura Oncology, Kyowa Kirin Pharm, Lilly, Loxo Oncology, Lytix Biopharma As, Medimmune, Menarini Ricerche, Merck Sharp & Dohme Chibret, Merrimack Pharmaceuticals, Merus, Millennium Pharmaceuticals, Nanobiotix, Nektar Therapeutics, Novartis Pharma, Octimet Oncology Nv, Oncoethix, Oncomed, Oncopeptides, Onyx Therapeutics, Orion Pharma, Oryzon Genomics, Pfizer, Pharma Mar, Pierre Fabre , Rigontec Gmbh, Roche, Sanofi Aventis, Sierra Oncology, Taiho Pharma, Tesaro, Inc, Tioma Therapeutics, Inc., Xencor; Research Grants from Astrazeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, Sanofi; Non-financial support (drug supplied) from Astrazeneca, Bayer, BMS, Boringher Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, Roche

      Maria-Rosa Ghigna ([email protected]) - no disclosures.

      Roberto Ferreira ([email protected]) - advisory board MSD, Beigene.

      Filippo Gustavo Dall'Olio ([email protected]) - no disclosures.

      Francesco Passiglia ([email protected]) - consultant fee from Astra Zeneca, Janssen, Amgen, Sanofi, Merck Sharp and Dohme, Beigene, Thermo Fisher Scientifics.

      Enriqueta Felip ([email protected]) - Advisory Board: Amgen, Astra Zeneca, Bayer, Bristol-Myers Squibb, Daichii Sankyo, Eli Lilly, F. Hoffmann-La Roche, Glaxo Smith Kline, Janssen, Merck Sharp &Dohme, Merck Serono, Novartis, Peptomyc, Pfizer, Sanofi, Takeda; Invited Speaker: Amgen, Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, F. Hoffmann-La Roche, Janssen, Medscape, Merck Sharp & Dohme, Peervoice, Pfizer, Medical Trends, Merck Serono, Sanofi, Takeda, Touchoncology; Research Funding: Merck Healthcare Kgaa, Fundación Merck Salud.

      Vienna Ludovini ([email protected]) – no disclosures.

      Fabrice Barlesi ([email protected]) - Personal financial interests - Astra-Zeneca, Bayer, Bristol-Myers Squibb, Boehringer–Ingelheim, Eli Lilly Oncology, F. Hoffmann–La Roche Ltd, Novartis, Merck, Mirati, MSD, Pierre Fabre, Pfizer, Seattle Genetics and Takeda.

      David Planchard ([email protected]) - Consulting, advisory role or lectures: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Daiichi Sankyo, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche. Honoraria: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Celgene, Eli Lilly, Merck, Novartis, Pfizer, prIME Oncology, Peer CME, Roche. Clinical trials research: AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Pfizer, Roche, Medimmun, Sanofi-Aventis, Taiho Pharma, Novocure, Daiichi Sankyo. Travel, Accommodations, Expenses: AstraZeneca, Roche, Novartis, prIME Oncology, Pfizer.

      Benjamin Besse ([email protected]) - Sponsored Research at Gustave Roussy Cancer Center: Abbvie, Amgen, AstraZeneca, Biogen, Blueprint Medicines, BMS, Celgene, Eli Lilly, GSK, Ignyta, IPSEN, Merck KGaA, MSD, Nektar, Onxeo, Pfizer, Pharma Mar, Sanofi, Spectrum Pharmaceuticals, Takeda, Tiziana Pharma. Investigator or co-investigator of trials: Nerviano, GSK, Pfizer, Roche-Genentech, Lilly, OSE Pharma, MSD, Celgene, Stemcentrx, Ignyta, Abbvie, Loxo Oncology, AstraZeneca, Blueprint Medicines.

      CRediT Authorship Contribution Statement

      Mihaela Aldea: Concept, Methodology, Data curation, Investigation, Formal analysis, Writing - original draft, Writing - review & editing.

      Arianna Marinello: Data curation, Investigation, Methodology, Writing - review & editing.

      Wael Zrafi: Data curation, Methodology, Statistical analysis, Writing - review & editing.

      Michael Duruisseaux, Nicole Conci, Giacomo Massa, Giulio Metro, Isabelle Monnet, Patricia Iranzo Gomez, Fabrizio Tabbo, Emilio Bria, Florian Guisier, Damien Vasseur, Colin R. Lindsay, Santiago Ponce, Sophie Cousin, Fabrizio Citarella, Vincent Fallet, Jose Nicolas Minatta, Anna Eisert, Hortense de Saint Basile, Clarisse Audigier-Valette, Laura Mezquita, Antonio Calles, Giannis Mountzios, Marco Tagliamento , Jordi Remon Masip, Judith Raimbourg, Safae Terrisse, Alexandro Russo, Diego Cortinovis, Philippe Rochigneux, David James Pinato, Alessio Cortellini, Camille Leonce, Anas Gazzah, Maria-Rosa Ghigna, Roberto Ferrara, Filippo Gustavo Dall'Olio, Francesco Passiglia, Vienna Ludovini, Fabrice Barlesi, Enriqueta Felip, David Planchard : Investigation, Methodology, Writing - review & editing.

      Benjamin Besse: Concept, Methodology, Writing - review & editing, Supervision.

      Identification

      DOI: https://doi.org/10.1016/j.jtho.2022.12.018

      Copyright

      © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc.

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