Targeting RET in patients with RET-rearranged lung cancers: Results from the global, multicenter RET registry

Oliver Gautschi, Julie Milia, Thomas Filleron, Juergen Wolf, David P. Carbone, Dwight Owen, Ross Camidge, Vignhesh Narayanan, Robert C. Doebele, Benjamin Besse, Jordi Remon-Masip, Pasi A. Janne, Mark M. Awad, Nir Peled, Chul Cho Byoung, Daniel D. Karp, Michael Van Den Heuvel, Heather A. Wakelee, Joel W. Neal, Tony S.K. MokJames C.H. Yang, Sai Hong Ignatius Ou, Georg Pall, Patrizia Froesch, Gérard Zalcman, David R. Gandara, Jonathan W. Riess, Vamsidhar Velcheti, Kristin Zeidler, Joachim Diebold, Martin Früh, Sebastian Michels, Isabelle Monnet, Sanjay Popat, Rafael Rosell, Niki Karachaliou, Sacha I. Rothschild, Jin Yuan Shih, Arne Warth, Thomas Muley, Florian Cabillic, Julien Mazières, Alexander Drilon

Research output: Contribution to journalArticle

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Abstract

Purpose: In addition to prospective trials for non-small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods: A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement. Molecular profiling was performed locally by reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or nextgeneration sequencing. Anonymized data-clinical, pathologic, and molecular features-were collected centrally and analyzed by an independent statistician. Best response to RET tyrosine kinase inhibition administered outside of a clinical trial was determined by RECIST v1.1. Results: By April 2016, 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States were accrued. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63%) with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent rearrangement was KIF5B-RET (72%). Of those patients, 53 received one or more RET tyrosine kinase inhibitors in sequence: cabozantinib (21 patients), vandetanib (11 patients), sunitinib (10 patients), sorafenib (two patients), alectinib (two patients), lenvatinib (two patients), nintedanib (two patients), ponatinib (two patients), and regorafenib (one patient). The rate of any complete or partial response to cabozantinib, vandetanib, and sunitinib was 37%, 18%, and 22%, respectively. Further responses were observed with lenvantinib and nintedanib. Median progression-free survival was 2.3 months (95% CI, 1.6 to 5.0 months), and median overall survival was 6.8 months (95% CI, 3.9 to 14.3 months). Conclusion: Available multikinase inhibitors had limited activity in patients with RET-rearranged NSCLC in this retrospective study. Further investigation of the biology of RET-rearranged lung cancers and identification of new targeted therapeutics will be required to improve outcomes for these patients.

Original languageEnglish
Pages (from-to)1403-1410
Number of pages8
JournalJournal of Clinical Oncology
Volume35
Issue number13
DOIs
Publication statusPublished - 2017 May 1

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Registries
Lung Neoplasms
Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Reverse Transcriptase Polymerase Chain Reaction
Fluorescence In Situ Hybridization
Disease-Free Survival
Thorax
Therapeutics
Retrospective Studies

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Gautschi, O., Milia, J., Filleron, T., Wolf, J., Carbone, D. P., Owen, D., ... Drilon, A. (2017). Targeting RET in patients with RET-rearranged lung cancers: Results from the global, multicenter RET registry. Journal of Clinical Oncology, 35(13), 1403-1410. https://doi.org/10.1200/JCO.2016.70.9352
Gautschi, Oliver ; Milia, Julie ; Filleron, Thomas ; Wolf, Juergen ; Carbone, David P. ; Owen, Dwight ; Camidge, Ross ; Narayanan, Vignhesh ; Doebele, Robert C. ; Besse, Benjamin ; Remon-Masip, Jordi ; Janne, Pasi A. ; Awad, Mark M. ; Peled, Nir ; Byoung, Chul Cho ; Karp, Daniel D. ; Van Den Heuvel, Michael ; Wakelee, Heather A. ; Neal, Joel W. ; Mok, Tony S.K. ; Yang, James C.H. ; Ou, Sai Hong Ignatius ; Pall, Georg ; Froesch, Patrizia ; Zalcman, Gérard ; Gandara, David R. ; Riess, Jonathan W. ; Velcheti, Vamsidhar ; Zeidler, Kristin ; Diebold, Joachim ; Früh, Martin ; Michels, Sebastian ; Monnet, Isabelle ; Popat, Sanjay ; Rosell, Rafael ; Karachaliou, Niki ; Rothschild, Sacha I. ; Shih, Jin Yuan ; Warth, Arne ; Muley, Thomas ; Cabillic, Florian ; Mazières, Julien ; Drilon, Alexander. / Targeting RET in patients with RET-rearranged lung cancers : Results from the global, multicenter RET registry. In: Journal of Clinical Oncology. 2017 ; Vol. 35, No. 13. pp. 1403-1410.
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title = "Targeting RET in patients with RET-rearranged lung cancers: Results from the global, multicenter RET registry",
abstract = "Purpose: In addition to prospective trials for non-small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods: A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement. Molecular profiling was performed locally by reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or nextgeneration sequencing. Anonymized data-clinical, pathologic, and molecular features-were collected centrally and analyzed by an independent statistician. Best response to RET tyrosine kinase inhibition administered outside of a clinical trial was determined by RECIST v1.1. Results: By April 2016, 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States were accrued. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63{\%}) with lung adenocarcinomas (98{\%}) and advanced disease (91{\%}). The most frequent rearrangement was KIF5B-RET (72{\%}). Of those patients, 53 received one or more RET tyrosine kinase inhibitors in sequence: cabozantinib (21 patients), vandetanib (11 patients), sunitinib (10 patients), sorafenib (two patients), alectinib (two patients), lenvatinib (two patients), nintedanib (two patients), ponatinib (two patients), and regorafenib (one patient). The rate of any complete or partial response to cabozantinib, vandetanib, and sunitinib was 37{\%}, 18{\%}, and 22{\%}, respectively. Further responses were observed with lenvantinib and nintedanib. Median progression-free survival was 2.3 months (95{\%} CI, 1.6 to 5.0 months), and median overall survival was 6.8 months (95{\%} CI, 3.9 to 14.3 months). Conclusion: Available multikinase inhibitors had limited activity in patients with RET-rearranged NSCLC in this retrospective study. Further investigation of the biology of RET-rearranged lung cancers and identification of new targeted therapeutics will be required to improve outcomes for these patients.",
author = "Oliver Gautschi and Julie Milia and Thomas Filleron and Juergen Wolf and Carbone, {David P.} and Dwight Owen and Ross Camidge and Vignhesh Narayanan and Doebele, {Robert C.} and Benjamin Besse and Jordi Remon-Masip and Janne, {Pasi A.} and Awad, {Mark M.} and Nir Peled and Byoung, {Chul Cho} and Karp, {Daniel D.} and {Van Den Heuvel}, Michael and Wakelee, {Heather A.} and Neal, {Joel W.} and Mok, {Tony S.K.} and Yang, {James C.H.} and Ou, {Sai Hong Ignatius} and Georg Pall and Patrizia Froesch and G{\'e}rard Zalcman and Gandara, {David R.} and Riess, {Jonathan W.} and Vamsidhar Velcheti and Kristin Zeidler and Joachim Diebold and Martin Fr{\"u}h and Sebastian Michels and Isabelle Monnet and Sanjay Popat and Rafael Rosell and Niki Karachaliou and Rothschild, {Sacha I.} and Shih, {Jin Yuan} and Arne Warth and Thomas Muley and Florian Cabillic and Julien Mazi{\`e}res and Alexander Drilon",
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Gautschi, O, Milia, J, Filleron, T, Wolf, J, Carbone, DP, Owen, D, Camidge, R, Narayanan, V, Doebele, RC, Besse, B, Remon-Masip, J, Janne, PA, Awad, MM, Peled, N, Byoung, CC, Karp, DD, Van Den Heuvel, M, Wakelee, HA, Neal, JW, Mok, TSK, Yang, JCH, Ou, SHI, Pall, G, Froesch, P, Zalcman, G, Gandara, DR, Riess, JW, Velcheti, V, Zeidler, K, Diebold, J, Früh, M, Michels, S, Monnet, I, Popat, S, Rosell, R, Karachaliou, N, Rothschild, SI, Shih, JY, Warth, A, Muley, T, Cabillic, F, Mazières, J & Drilon, A 2017, 'Targeting RET in patients with RET-rearranged lung cancers: Results from the global, multicenter RET registry', Journal of Clinical Oncology, vol. 35, no. 13, pp. 1403-1410. https://doi.org/10.1200/JCO.2016.70.9352

Targeting RET in patients with RET-rearranged lung cancers : Results from the global, multicenter RET registry. / Gautschi, Oliver; Milia, Julie; Filleron, Thomas; Wolf, Juergen; Carbone, David P.; Owen, Dwight; Camidge, Ross; Narayanan, Vignhesh; Doebele, Robert C.; Besse, Benjamin; Remon-Masip, Jordi; Janne, Pasi A.; Awad, Mark M.; Peled, Nir; Byoung, Chul Cho; Karp, Daniel D.; Van Den Heuvel, Michael; Wakelee, Heather A.; Neal, Joel W.; Mok, Tony S.K.; Yang, James C.H.; Ou, Sai Hong Ignatius; Pall, Georg; Froesch, Patrizia; Zalcman, Gérard; Gandara, David R.; Riess, Jonathan W.; Velcheti, Vamsidhar; Zeidler, Kristin; Diebold, Joachim; Früh, Martin; Michels, Sebastian; Monnet, Isabelle; Popat, Sanjay; Rosell, Rafael; Karachaliou, Niki; Rothschild, Sacha I.; Shih, Jin Yuan; Warth, Arne; Muley, Thomas; Cabillic, Florian; Mazières, Julien; Drilon, Alexander.

In: Journal of Clinical Oncology, Vol. 35, No. 13, 01.05.2017, p. 1403-1410.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Targeting RET in patients with RET-rearranged lung cancers

T2 - Results from the global, multicenter RET registry

AU - Gautschi, Oliver

AU - Milia, Julie

AU - Filleron, Thomas

AU - Wolf, Juergen

AU - Carbone, David P.

AU - Owen, Dwight

AU - Camidge, Ross

AU - Narayanan, Vignhesh

AU - Doebele, Robert C.

AU - Besse, Benjamin

AU - Remon-Masip, Jordi

AU - Janne, Pasi A.

AU - Awad, Mark M.

AU - Peled, Nir

AU - Byoung, Chul Cho

AU - Karp, Daniel D.

AU - Van Den Heuvel, Michael

AU - Wakelee, Heather A.

AU - Neal, Joel W.

AU - Mok, Tony S.K.

AU - Yang, James C.H.

AU - Ou, Sai Hong Ignatius

AU - Pall, Georg

AU - Froesch, Patrizia

AU - Zalcman, Gérard

AU - Gandara, David R.

AU - Riess, Jonathan W.

AU - Velcheti, Vamsidhar

AU - Zeidler, Kristin

AU - Diebold, Joachim

AU - Früh, Martin

AU - Michels, Sebastian

AU - Monnet, Isabelle

AU - Popat, Sanjay

AU - Rosell, Rafael

AU - Karachaliou, Niki

AU - Rothschild, Sacha I.

AU - Shih, Jin Yuan

AU - Warth, Arne

AU - Muley, Thomas

AU - Cabillic, Florian

AU - Mazières, Julien

AU - Drilon, Alexander

PY - 2017/5/1

Y1 - 2017/5/1

N2 - Purpose: In addition to prospective trials for non-small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods: A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement. Molecular profiling was performed locally by reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or nextgeneration sequencing. Anonymized data-clinical, pathologic, and molecular features-were collected centrally and analyzed by an independent statistician. Best response to RET tyrosine kinase inhibition administered outside of a clinical trial was determined by RECIST v1.1. Results: By April 2016, 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States were accrued. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63%) with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent rearrangement was KIF5B-RET (72%). Of those patients, 53 received one or more RET tyrosine kinase inhibitors in sequence: cabozantinib (21 patients), vandetanib (11 patients), sunitinib (10 patients), sorafenib (two patients), alectinib (two patients), lenvatinib (two patients), nintedanib (two patients), ponatinib (two patients), and regorafenib (one patient). The rate of any complete or partial response to cabozantinib, vandetanib, and sunitinib was 37%, 18%, and 22%, respectively. Further responses were observed with lenvantinib and nintedanib. Median progression-free survival was 2.3 months (95% CI, 1.6 to 5.0 months), and median overall survival was 6.8 months (95% CI, 3.9 to 14.3 months). Conclusion: Available multikinase inhibitors had limited activity in patients with RET-rearranged NSCLC in this retrospective study. Further investigation of the biology of RET-rearranged lung cancers and identification of new targeted therapeutics will be required to improve outcomes for these patients.

AB - Purpose: In addition to prospective trials for non-small-cell lung cancers (NSCLCs) that are driven by less common genomic alterations, registries provide complementary information on patient response to targeted therapies. Here, we present the results of an international registry of patients with RET-rearranged NSCLCs, providing the largest data set, to our knowledge, on outcomes of RET-directed therapy thus far. Methods: A global, multicenter network of thoracic oncologists identified patients with pathologically confirmed NSCLC that harbored a RET rearrangement. Molecular profiling was performed locally by reverse transcriptase polymerase chain reaction, fluorescence in situ hybridization, or nextgeneration sequencing. Anonymized data-clinical, pathologic, and molecular features-were collected centrally and analyzed by an independent statistician. Best response to RET tyrosine kinase inhibition administered outside of a clinical trial was determined by RECIST v1.1. Results: By April 2016, 165 patients with RET-rearranged NSCLC from 29 centers across Europe, Asia, and the United States were accrued. Median age was 61 years (range, 29 to 89 years). The majority of patients were never smokers (63%) with lung adenocarcinomas (98%) and advanced disease (91%). The most frequent rearrangement was KIF5B-RET (72%). Of those patients, 53 received one or more RET tyrosine kinase inhibitors in sequence: cabozantinib (21 patients), vandetanib (11 patients), sunitinib (10 patients), sorafenib (two patients), alectinib (two patients), lenvatinib (two patients), nintedanib (two patients), ponatinib (two patients), and regorafenib (one patient). The rate of any complete or partial response to cabozantinib, vandetanib, and sunitinib was 37%, 18%, and 22%, respectively. Further responses were observed with lenvantinib and nintedanib. Median progression-free survival was 2.3 months (95% CI, 1.6 to 5.0 months), and median overall survival was 6.8 months (95% CI, 3.9 to 14.3 months). Conclusion: Available multikinase inhibitors had limited activity in patients with RET-rearranged NSCLC in this retrospective study. Further investigation of the biology of RET-rearranged lung cancers and identification of new targeted therapeutics will be required to improve outcomes for these patients.

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DO - 10.1200/JCO.2016.70.9352

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