Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors

François Doz; Cornelis M. Van Tilburg; Birgit Geoerger; Martin Højgaard; Ingrid Øra; Valentina Boni; Michael Capra; Julia Chisholm; Hyun Cheol Chung; Steven G. Dubois; Soledad Gallego-Melcon; Nicolas U. Gerber; Hiroaki Goto; Juneko E. Grilley-Olson; Jordan R. Hansford; David S. Hong; Antoine Italiano; Hyoung Jin Kang; Karsten Nysom; Anne Thorwarth; Joanna Stefanowicz; Makoto Tahara; David S. Ziegler; Igor T. Gavrilovic; Ricarda Norenberg; Laura Dima; Esther De La Cuesta; Theodore W. Laetsch; Alexander Drilon; Sebastien Perreault

doi:10.1093/neuonc/noab274

Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors

François Doz, Cornelis M. Van Tilburg, Birgit Geoerger, Martin Højgaard, Ingrid Øra, Valentina Boni, Michael Capra, Julia Chisholm, Hyun Cheol Chung, Steven G. Dubois, Soledad Gallego-Melcon, Nicolas U. Gerber, Hiroaki Goto, Juneko E. Grilley-Olson, Jordan R. Hansford, David S. Hong, Antoine Italiano, Hyoung Jin Kang, Karsten Nysom, Anne ThorwarthJoanna Stefanowicz, Makoto Tahara, David S. Ziegler, Igor T. Gavrilovic, Ricarda Norenberg, Laura Dima, Esther De La Cuesta, Theodore W. Laetsch, Alexander Drilon, Sebastien Perreault

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

26 Citations (Scopus)

Abstract

Background: Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved to treat adult and pediatric patients with TRK fusion-positive cancer. The aim of this study was to evaluate the efficacy and safety of larotrectinib in patients with TRK fusion-positive primary central nervous system (CNS) tumors. Methods: Patients with TRK fusion-positive primary CNS tumors from two clinical trials (NCT02637687, NCT02576431) were identified. The primary endpoint was investigator-assessed objective response rate (ORR). Results: As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified (median age: 8.9 years; range: 1.3-79.0). The most common histologies were high-grade glioma (HGG; n = 19) and low-grade glioma (LGG; n = 8). ORR was 30% (95% confidence interval [CI]: 16-49) for all patients. The 24-week disease control rate was 73% (95% CI: 54-87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The 12-month rates for duration of response, progression-free survival, and overall survival were 75% (95% CI: 45-100), 56% (95% CI: 38-74), and 85% (95% CI: 71-99), respectively. Median time to response was 1.9 months (range 1.0-3.8 months). Duration of treatment ranged from 1.2-31.3+ months. Treatment-related adverse events were reported for 20 patients, with grade 3-4 in 3 patients. No new safety signals were identified. Conclusions: In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile.

Original language	English
Pages (from-to)	997-1007
Number of pages	11
Journal	Neuro-Oncology
Volume	24
Issue number	6
DOIs	https://doi.org/10.1093/neuonc/noab274
Publication status	Published - 2022 Jun 1

Bibliographical note

Funding Information:
National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden National Health Service Foundation Trust and the Institute of Cancer Research, London to J.C.

Publisher Copyright:
© 2021 The Author(s). Published by Oxford University Press on behalf of the Society for Neuro-Oncology.

All Science Journal Classification (ASJC) codes

Oncology
Clinical Neurology
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1093/neuonc/noab274

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Doz, F., Van Tilburg, C. M., Geoerger, B., Højgaard, M., Øra, I., Boni, V., Capra, M., Chisholm, J., Chung, H. C., Dubois, S. G., Gallego-Melcon, S., Gerber, N. U., Goto, H., Grilley-Olson, J. E., Hansford, J. R., Hong, D. S., Italiano, A., Kang, H. J., Nysom, K., ... Perreault, S. (2022). Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors. Neuro-Oncology, 24(6), 997-1007. https://doi.org/10.1093/neuonc/noab274

@article{77bf279e161f40fba56c9f9a7ecd1ba7,

title = "Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors",

abstract = "Background: Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved to treat adult and pediatric patients with TRK fusion-positive cancer. The aim of this study was to evaluate the efficacy and safety of larotrectinib in patients with TRK fusion-positive primary central nervous system (CNS) tumors. Methods: Patients with TRK fusion-positive primary CNS tumors from two clinical trials (NCT02637687, NCT02576431) were identified. The primary endpoint was investigator-assessed objective response rate (ORR). Results: As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified (median age: 8.9 years; range: 1.3-79.0). The most common histologies were high-grade glioma (HGG; n = 19) and low-grade glioma (LGG; n = 8). ORR was 30% (95% confidence interval [CI]: 16-49) for all patients. The 24-week disease control rate was 73% (95% CI: 54-87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The 12-month rates for duration of response, progression-free survival, and overall survival were 75% (95% CI: 45-100), 56% (95% CI: 38-74), and 85% (95% CI: 71-99), respectively. Median time to response was 1.9 months (range 1.0-3.8 months). Duration of treatment ranged from 1.2-31.3+ months. Treatment-related adverse events were reported for 20 patients, with grade 3-4 in 3 patients. No new safety signals were identified. Conclusions: In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile.",

author = "Fran{\c c}ois Doz and {Van Tilburg}, {Cornelis M.} and Birgit Geoerger and Martin H{\o}jgaard and Ingrid {\O}ra and Valentina Boni and Michael Capra and Julia Chisholm and Chung, {Hyun Cheol} and Dubois, {Steven G.} and Soledad Gallego-Melcon and Gerber, {Nicolas U.} and Hiroaki Goto and Grilley-Olson, {Juneko E.} and Hansford, {Jordan R.} and Hong, {David S.} and Antoine Italiano and Kang, {Hyoung Jin} and Karsten Nysom and Anne Thorwarth and Joanna Stefanowicz and Makoto Tahara and Ziegler, {David S.} and Gavrilovic, {Igor T.} and Ricarda Norenberg and Laura Dima and {De La Cuesta}, Esther and Laetsch, {Theodore W.} and Alexander Drilon and Sebastien Perreault",

note = "Funding Information: National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden National Health Service Foundation Trust and the Institute of Cancer Research, London to J.C. Publisher Copyright: {\textcopyright} 2021 The Author(s). Published by Oxford University Press on behalf of the Society for Neuro-Oncology.",

year = "2022",

month = jun,

day = "1",

doi = "10.1093/neuonc/noab274",

language = "English",

volume = "24",

pages = "997--1007",

journal = "Neuro-Oncology",

issn = "1522-8517",

publisher = "Oxford University Press",

number = "6",

}

Doz, F, Van Tilburg, CM, Geoerger, B, Højgaard, M, Øra, I, Boni, V, Capra, M, Chisholm, J, Chung, HC, Dubois, SG, Gallego-Melcon, S, Gerber, NU, Goto, H, Grilley-Olson, JE, Hansford, JR, Hong, DS, Italiano, A, Kang, HJ, Nysom, K, Thorwarth, A, Stefanowicz, J, Tahara, M, Ziegler, DS, Gavrilovic, IT, Norenberg, R, Dima, L, De La Cuesta, E, Laetsch, TW, Drilon, A & Perreault, S 2022, 'Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors', Neuro-Oncology, vol. 24, no. 6, pp. 997-1007. https://doi.org/10.1093/neuonc/noab274

TY - JOUR

T1 - Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors

AU - Doz, François

AU - Van Tilburg, Cornelis M.

AU - Geoerger, Birgit

AU - Højgaard, Martin

AU - Øra, Ingrid

AU - Boni, Valentina

AU - Capra, Michael

AU - Chisholm, Julia

AU - Chung, Hyun Cheol

AU - Dubois, Steven G.

AU - Gallego-Melcon, Soledad

AU - Gerber, Nicolas U.

AU - Goto, Hiroaki

AU - Grilley-Olson, Juneko E.

AU - Hansford, Jordan R.

AU - Hong, David S.

AU - Italiano, Antoine

AU - Kang, Hyoung Jin

AU - Nysom, Karsten

AU - Thorwarth, Anne

AU - Stefanowicz, Joanna

AU - Tahara, Makoto

AU - Ziegler, David S.

AU - Gavrilovic, Igor T.

AU - Norenberg, Ricarda

AU - Dima, Laura

AU - De La Cuesta, Esther

AU - Laetsch, Theodore W.

AU - Drilon, Alexander

AU - Perreault, Sebastien

N1 - Funding Information: National Institute for Health Research (NIHR) Biomedical Research Centre at The Royal Marsden National Health Service Foundation Trust and the Institute of Cancer Research, London to J.C. Publisher Copyright: © 2021 The Author(s). Published by Oxford University Press on behalf of the Society for Neuro-Oncology.

PY - 2022/6/1

Y1 - 2022/6/1

N2 - Background: Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved to treat adult and pediatric patients with TRK fusion-positive cancer. The aim of this study was to evaluate the efficacy and safety of larotrectinib in patients with TRK fusion-positive primary central nervous system (CNS) tumors. Methods: Patients with TRK fusion-positive primary CNS tumors from two clinical trials (NCT02637687, NCT02576431) were identified. The primary endpoint was investigator-assessed objective response rate (ORR). Results: As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified (median age: 8.9 years; range: 1.3-79.0). The most common histologies were high-grade glioma (HGG; n = 19) and low-grade glioma (LGG; n = 8). ORR was 30% (95% confidence interval [CI]: 16-49) for all patients. The 24-week disease control rate was 73% (95% CI: 54-87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The 12-month rates for duration of response, progression-free survival, and overall survival were 75% (95% CI: 45-100), 56% (95% CI: 38-74), and 85% (95% CI: 71-99), respectively. Median time to response was 1.9 months (range 1.0-3.8 months). Duration of treatment ranged from 1.2-31.3+ months. Treatment-related adverse events were reported for 20 patients, with grade 3-4 in 3 patients. No new safety signals were identified. Conclusions: In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile.

AB - Background: Larotrectinib is a first-in-class, highly selective tropomyosin receptor kinase (TRK) inhibitor approved to treat adult and pediatric patients with TRK fusion-positive cancer. The aim of this study was to evaluate the efficacy and safety of larotrectinib in patients with TRK fusion-positive primary central nervous system (CNS) tumors. Methods: Patients with TRK fusion-positive primary CNS tumors from two clinical trials (NCT02637687, NCT02576431) were identified. The primary endpoint was investigator-assessed objective response rate (ORR). Results: As of July 2020, 33 patients with TRK fusion-positive CNS tumors were identified (median age: 8.9 years; range: 1.3-79.0). The most common histologies were high-grade glioma (HGG; n = 19) and low-grade glioma (LGG; n = 8). ORR was 30% (95% confidence interval [CI]: 16-49) for all patients. The 24-week disease control rate was 73% (95% CI: 54-87). Twenty-three of 28 patients (82%) with measurable disease had tumor shrinkage. The 12-month rates for duration of response, progression-free survival, and overall survival were 75% (95% CI: 45-100), 56% (95% CI: 38-74), and 85% (95% CI: 71-99), respectively. Median time to response was 1.9 months (range 1.0-3.8 months). Duration of treatment ranged from 1.2-31.3+ months. Treatment-related adverse events were reported for 20 patients, with grade 3-4 in 3 patients. No new safety signals were identified. Conclusions: In patients with TRK fusion-positive CNS tumors, larotrectinib demonstrated rapid and durable responses, high disease control rate, and a favorable safety profile.

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DO - 10.1093/neuonc/noab274

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Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors

Abstract

Bibliographical note

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UN SDGs

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