Updated efficacy and safety of entrectinib in NTRK fusion-positive non-small cell lung cancer

Byoung Chul Cho; Chao Hua Chiu; Erminia Massarelli; Gary L. Buchschacher; Koichi Goto; Tobias R. Overbeck; Herbert H.F. Loong; Cheng E. Chee; Pilar Garrido; Xiaorong Dong; Yun Fan; Shun Lu; Sven Schwemmers; Walter Bordogna; Harald Zeuner; Stuart Osborne; Thomas John

doi:10.1016/j.lungcan.2023.107442

Updated efficacy and safety of entrectinib in NTRK fusion-positive non-small cell lung cancer

Byoung Chul Cho, Chao Hua Chiu, Erminia Massarelli, Gary L. Buchschacher, Koichi Goto, Tobias R. Overbeck, Herbert H.F. Loong, Cheng E. Chee, Pilar Garrido, Xiaorong Dong, Yun Fan, Shun Lu, Sven Schwemmers, Walter Bordogna, Harald Zeuner, Stuart Osborne, Thomas John

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

6 Citations (Scopus)

Abstract

Objectives: NTRK fusions result in constitutively active oncogenic TRK proteins responsible for ∼ 0.2 % of non-small cell lung cancer (NSCLC) cases. Approximately 40 % of patients with advanced NSCLC develop CNS metastases; therefore, treatments with intracranial (IC) efficacy are needed. In an integrated analysis of three phase I/II studies (ALKA-372–001: EudraCT 2012–000148–88; STARTRK-1: NCT02097810; STARTRK-2: NCT02568267), entrectinib, a potent, CNS-active, TRK inhibitor, demonstrated efficacy in patients with NTRK fusion-positive (fp) NSCLC (objective response rate [ORR]: 64.5 %; 2 August 2021 data cut-off). We present updated data for this cohort. Materials and methods: Eligible patients were ≥ 18 years with locally advanced/metastatic, NTRK-fp NSCLC with ≥ 12 months of follow-up. Tumor responses were assessed by blinded independent central review (BICR) per RECIST v1.1 at Week 4 and every eight weeks thereafter. Co-primary endpoints: ORR; duration of response (DoR). Secondary endpoints included progression-free survival (PFS); overall survival (OS); IC efficacy; safety. Enrolment cut-off: 2 July 2021; data cut-off: 2 August 2022. Results: The efficacy-evaluable population included 51 patients with NTRK-fp NSCLC. Median age was 60.0 years (range 22–88); 20 patients (39.2 %) had investigator-assessed baseline CNS metastases. Median survival follow–up was 26.3 months (95 % CI 21.0–34.1). ORR was 62.7 % (95 % CI 48.1–75.9), with six complete and 26 partial responses. Median DoR and PFS were 27.3 months (95 % CI 19.9–30.9) and 28.0 months (95 % CI 15.7–30.4), respectively. Median OS was 41.5 months. In patients with BICR-assessed baseline CNS metastases, IC-ORR was 64.3 % (n = 9/14; 95 % CI 35.1–87.2), including seven complete responders, and IC-DoR was 55.7 months. In the safety–evaluable population (n = 55), most treatment-related adverse events were grade 1/2; no treatment-related deaths were reported. Conclusion: Entrectinib has continued to demonstrate deep and durable systemic and IC responses in patients with NTRK-fp NSCLC.

Original language	English
Article number	107442
Journal	Lung Cancer
Volume	188
DOIs	https://doi.org/10.1016/j.lungcan.2023.107442
Publication status	Published - Feb 2024

Keywords

CNS
Entrectinib
Intracranial
NSCLC
NTRK fusions

ASJC Scopus subject areas

Oncology
Pulmonary and Respiratory Medicine
Cancer Research

UN SDGs

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

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10.1016/j.lungcan.2023.107442

Cite this

Cho, B. C., Chiu, C. H., Massarelli, E., Buchschacher, G. L., Goto, K., Overbeck, T. R., Loong, H. H. F., Chee, C. E., Garrido, P., Dong, X., Fan, Y., Lu, S., Schwemmers, S., Bordogna, W., Zeuner, H., Osborne, S., & John, T. (2024). Updated efficacy and safety of entrectinib in NTRK fusion-positive non-small cell lung cancer. Lung Cancer, 188, Article 107442. https://doi.org/10.1016/j.lungcan.2023.107442

Cho, BC, Chiu, CH, Massarelli, E, Buchschacher, GL, Goto, K, Overbeck, TR, Loong, HHF, Chee, CE, Garrido, P, Dong, X, Fan, Y, Lu, S, Schwemmers, S, Bordogna, W, Zeuner, H, Osborne, S & John, T 2024, 'Updated efficacy and safety of entrectinib in NTRK fusion-positive non-small cell lung cancer', Lung Cancer, vol. 188, 107442. https://doi.org/10.1016/j.lungcan.2023.107442

@article{cfec81bd8c2d483cafe6957f986564aa,

title = "Updated efficacy and safety of entrectinib in NTRK fusion-positive non-small cell lung cancer",

abstract = "Objectives: NTRK fusions result in constitutively active oncogenic TRK proteins responsible for ∼ 0.2 % of non-small cell lung cancer (NSCLC) cases. Approximately 40 % of patients with advanced NSCLC develop CNS metastases; therefore, treatments with intracranial (IC) efficacy are needed. In an integrated analysis of three phase I/II studies (ALKA-372–001: EudraCT 2012–000148–88; STARTRK-1: NCT02097810; STARTRK-2: NCT02568267), entrectinib, a potent, CNS-active, TRK inhibitor, demonstrated efficacy in patients with NTRK fusion-positive (fp) NSCLC (objective response rate [ORR]: 64.5 %; 2 August 2021 data cut-off). We present updated data for this cohort. Materials and methods: Eligible patients were ≥ 18 years with locally advanced/metastatic, NTRK-fp NSCLC with ≥ 12 months of follow-up. Tumor responses were assessed by blinded independent central review (BICR) per RECIST v1.1 at Week 4 and every eight weeks thereafter. Co-primary endpoints: ORR; duration of response (DoR). Secondary endpoints included progression-free survival (PFS); overall survival (OS); IC efficacy; safety. Enrolment cut-off: 2 July 2021; data cut-off: 2 August 2022. Results: The efficacy-evaluable population included 51 patients with NTRK-fp NSCLC. Median age was 60.0 years (range 22–88); 20 patients (39.2 %) had investigator-assessed baseline CNS metastases. Median survival follow–up was 26.3 months (95 % CI 21.0–34.1). ORR was 62.7 % (95 % CI 48.1–75.9), with six complete and 26 partial responses. Median DoR and PFS were 27.3 months (95 % CI 19.9–30.9) and 28.0 months (95 % CI 15.7–30.4), respectively. Median OS was 41.5 months. In patients with BICR-assessed baseline CNS metastases, IC-ORR was 64.3 % (n = 9/14; 95 % CI 35.1–87.2), including seven complete responders, and IC-DoR was 55.7 months. In the safety–evaluable population (n = 55), most treatment-related adverse events were grade 1/2; no treatment-related deaths were reported. Conclusion: Entrectinib has continued to demonstrate deep and durable systemic and IC responses in patients with NTRK-fp NSCLC.",

keywords = "CNS, Entrectinib, Intracranial, NSCLC, NTRK fusions",

author = "Cho, {Byoung Chul} and Chiu, {Chao Hua} and Erminia Massarelli and Buchschacher, {Gary L.} and Koichi Goto and Overbeck, {Tobias R.} and Loong, {Herbert H.F.} and Chee, {Cheng E.} and Pilar Garrido and Xiaorong Dong and Yun Fan and Shun Lu and Sven Schwemmers and Walter Bordogna and Harald Zeuner and Stuart Osborne and Thomas John",

note = "Publisher Copyright: {\textcopyright} 2023",

year = "2024",

month = feb,

doi = "10.1016/j.lungcan.2023.107442",

language = "English",

volume = "188",

journal = "Lung Cancer",

issn = "0169-5002",

publisher = "Elsevier Ireland Ltd",

}

TY - JOUR

T1 - Updated efficacy and safety of entrectinib in NTRK fusion-positive non-small cell lung cancer

AU - Cho, Byoung Chul

AU - Chiu, Chao Hua

AU - Massarelli, Erminia

AU - Buchschacher, Gary L.

AU - Goto, Koichi

AU - Overbeck, Tobias R.

AU - Loong, Herbert H.F.

AU - Chee, Cheng E.

AU - Garrido, Pilar

AU - Dong, Xiaorong

AU - Fan, Yun

AU - Lu, Shun

AU - Schwemmers, Sven

AU - Bordogna, Walter

AU - Zeuner, Harald

AU - Osborne, Stuart

AU - John, Thomas

PY - 2024/2

Y1 - 2024/2

N2 - Objectives: NTRK fusions result in constitutively active oncogenic TRK proteins responsible for ∼ 0.2 % of non-small cell lung cancer (NSCLC) cases. Approximately 40 % of patients with advanced NSCLC develop CNS metastases; therefore, treatments with intracranial (IC) efficacy are needed. In an integrated analysis of three phase I/II studies (ALKA-372–001: EudraCT 2012–000148–88; STARTRK-1: NCT02097810; STARTRK-2: NCT02568267), entrectinib, a potent, CNS-active, TRK inhibitor, demonstrated efficacy in patients with NTRK fusion-positive (fp) NSCLC (objective response rate [ORR]: 64.5 %; 2 August 2021 data cut-off). We present updated data for this cohort. Materials and methods: Eligible patients were ≥ 18 years with locally advanced/metastatic, NTRK-fp NSCLC with ≥ 12 months of follow-up. Tumor responses were assessed by blinded independent central review (BICR) per RECIST v1.1 at Week 4 and every eight weeks thereafter. Co-primary endpoints: ORR; duration of response (DoR). Secondary endpoints included progression-free survival (PFS); overall survival (OS); IC efficacy; safety. Enrolment cut-off: 2 July 2021; data cut-off: 2 August 2022. Results: The efficacy-evaluable population included 51 patients with NTRK-fp NSCLC. Median age was 60.0 years (range 22–88); 20 patients (39.2 %) had investigator-assessed baseline CNS metastases. Median survival follow–up was 26.3 months (95 % CI 21.0–34.1). ORR was 62.7 % (95 % CI 48.1–75.9), with six complete and 26 partial responses. Median DoR and PFS were 27.3 months (95 % CI 19.9–30.9) and 28.0 months (95 % CI 15.7–30.4), respectively. Median OS was 41.5 months. In patients with BICR-assessed baseline CNS metastases, IC-ORR was 64.3 % (n = 9/14; 95 % CI 35.1–87.2), including seven complete responders, and IC-DoR was 55.7 months. In the safety–evaluable population (n = 55), most treatment-related adverse events were grade 1/2; no treatment-related deaths were reported. Conclusion: Entrectinib has continued to demonstrate deep and durable systemic and IC responses in patients with NTRK-fp NSCLC.

AB - Objectives: NTRK fusions result in constitutively active oncogenic TRK proteins responsible for ∼ 0.2 % of non-small cell lung cancer (NSCLC) cases. Approximately 40 % of patients with advanced NSCLC develop CNS metastases; therefore, treatments with intracranial (IC) efficacy are needed. In an integrated analysis of three phase I/II studies (ALKA-372–001: EudraCT 2012–000148–88; STARTRK-1: NCT02097810; STARTRK-2: NCT02568267), entrectinib, a potent, CNS-active, TRK inhibitor, demonstrated efficacy in patients with NTRK fusion-positive (fp) NSCLC (objective response rate [ORR]: 64.5 %; 2 August 2021 data cut-off). We present updated data for this cohort. Materials and methods: Eligible patients were ≥ 18 years with locally advanced/metastatic, NTRK-fp NSCLC with ≥ 12 months of follow-up. Tumor responses were assessed by blinded independent central review (BICR) per RECIST v1.1 at Week 4 and every eight weeks thereafter. Co-primary endpoints: ORR; duration of response (DoR). Secondary endpoints included progression-free survival (PFS); overall survival (OS); IC efficacy; safety. Enrolment cut-off: 2 July 2021; data cut-off: 2 August 2022. Results: The efficacy-evaluable population included 51 patients with NTRK-fp NSCLC. Median age was 60.0 years (range 22–88); 20 patients (39.2 %) had investigator-assessed baseline CNS metastases. Median survival follow–up was 26.3 months (95 % CI 21.0–34.1). ORR was 62.7 % (95 % CI 48.1–75.9), with six complete and 26 partial responses. Median DoR and PFS were 27.3 months (95 % CI 19.9–30.9) and 28.0 months (95 % CI 15.7–30.4), respectively. Median OS was 41.5 months. In patients with BICR-assessed baseline CNS metastases, IC-ORR was 64.3 % (n = 9/14; 95 % CI 35.1–87.2), including seven complete responders, and IC-DoR was 55.7 months. In the safety–evaluable population (n = 55), most treatment-related adverse events were grade 1/2; no treatment-related deaths were reported. Conclusion: Entrectinib has continued to demonstrate deep and durable systemic and IC responses in patients with NTRK-fp NSCLC.

KW - CNS

KW - Entrectinib

KW - Intracranial

KW - NSCLC

KW - NTRK fusions

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DO - 10.1016/j.lungcan.2023.107442

M3 - Article

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SN - 0169-5002

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JO - Lung Cancer

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ER -

Updated efficacy and safety of entrectinib in NTRK fusion-positive non-small cell lung cancer

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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