Characteristics and Outcome of ROS1-Positive Non–Small Cell Lung Cancer Patients in Routine Clinical Practice

Sehhoon Park, Beung Chul Ahn, Sung Won Lim, Jong Mu Sun, Hye Ryun Kim, Min Hee Hong, Se Hoon Lee, Jin Seok Ahn, Keunchil Park, Yoon La Choi, ByoungChul Cho, Myung Ju Ahn

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Abstract

Introduction: ROS1-rearranged NSCLC is classified as a distinct molecular subset of NSCLC with a therapeutic target. ROS1 rearrangement is most often identified in never-smokers with adenocarcinoma and EGFR and ALK receptor tyrosine kinase gene (ALK) wild type. Treatment with tyrosine kinase inhibitors (TKIs), which target the ROS1 kinase domain, is considered the standard of care. TKIs have been shown to have a robust and durable response. However, information regarding the clinical outcomes of TKI treatment, including brain metastasis, remains limited. Methods: We identified 103 consecutive cases of ROS1-positive NSCLC by using break-apart fluorescence in situ hybridization (n = 84), next-generation sequencing (n = 23), or both (n = 3). Information regarding fusion breakpoints was available for eight patients. Clinical data, including patient characteristics, incidence of brain metastasis, response to chemotherapy, or to TKIs, were retrospectively analyzed. Results: The median patient age was 56 years, and 58.9% of the patients were female. Most of the patients (75.7%) were never-smokers. Adenocarcinoma was predominant (98.1%), and two cases with pleomorphic carcinoma were identified. Sixty percent of patients had an extrathoracic metastatic lesion, and 22% had an intracranial lesion at the initial presentation or at the time of recurrence. The median time to development of brain metastases was 12.0 months (range 2.1–84.1). The most common fusion partner was CD74 molecule gene (CD74), followed by syndecan 4 gene (SDC4), ezrin gene (EZR), tropomyosin 3 gene (TPM3), TRK-fused gene (TFG), zinc finger CCHC-type containing 8 gene (ZCCHC8), sacrolemma associated protein gene (SLMAP), and myosin VC gene (MYO5C). All of these fusion partners preserved the tyrosine kinase domain of ROS1. The median overall survival time was 52.1 months (95% confidence interval [CI]: 23.6–not reached). In the 90 patients who were treated with pemetrexed-based chemotherapy, the overall response rate and progression-free survival time were 53.3% and 8.0 months (95% CI: 6.4–11.7), respectively. The overall response rate and progression-free survival time were 70.7% and 12.7 months (95% CI: 8.1–21.8), respectively, for the 50 patients treated with TKIs. Brain metastasis was more often observed during TKI treatment (15.5%) than during pemetrexed-based chemotherapy (6.7%). Conclusions: ROS1-positive NSCLC has distinct clinical characteristics, with an effective and durable response to both TKIs and pemetrexed-based chemotherapies. Regardless, given its novel characteristics and distinct clinical responses to conventional chemotherapies and TKIs, the treatment strategy for ROS1-positive NSCLC remains to be further developed.

Original languageEnglish
Pages (from-to)1373-1382
Number of pages10
JournalJournal of Thoracic Oncology
Volume13
Issue number9
DOIs
Publication statusPublished - 2018 Sep 1

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Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Pemetrexed
Genes
Drug Therapy
Neoplasm Metastasis
Brain
Confidence Intervals
Disease-Free Survival
Adenocarcinoma
Syndecan-4
Therapeutics
Tropomyosin
Zinc Fingers
Myosins
Standard of Care
Fluorescence In Situ Hybridization
Phosphotransferases
Carcinoma
Recurrence

All Science Journal Classification (ASJC) codes

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Park, Sehhoon ; Ahn, Beung Chul ; Lim, Sung Won ; Sun, Jong Mu ; Kim, Hye Ryun ; Hong, Min Hee ; Lee, Se Hoon ; Ahn, Jin Seok ; Park, Keunchil ; Choi, Yoon La ; Cho, ByoungChul ; Ahn, Myung Ju. / Characteristics and Outcome of ROS1-Positive Non–Small Cell Lung Cancer Patients in Routine Clinical Practice. In: Journal of Thoracic Oncology. 2018 ; Vol. 13, No. 9. pp. 1373-1382.
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title = "Characteristics and Outcome of ROS1-Positive Non–Small Cell Lung Cancer Patients in Routine Clinical Practice",
abstract = "Introduction: ROS1-rearranged NSCLC is classified as a distinct molecular subset of NSCLC with a therapeutic target. ROS1 rearrangement is most often identified in never-smokers with adenocarcinoma and EGFR and ALK receptor tyrosine kinase gene (ALK) wild type. Treatment with tyrosine kinase inhibitors (TKIs), which target the ROS1 kinase domain, is considered the standard of care. TKIs have been shown to have a robust and durable response. However, information regarding the clinical outcomes of TKI treatment, including brain metastasis, remains limited. Methods: We identified 103 consecutive cases of ROS1-positive NSCLC by using break-apart fluorescence in situ hybridization (n = 84), next-generation sequencing (n = 23), or both (n = 3). Information regarding fusion breakpoints was available for eight patients. Clinical data, including patient characteristics, incidence of brain metastasis, response to chemotherapy, or to TKIs, were retrospectively analyzed. Results: The median patient age was 56 years, and 58.9{\%} of the patients were female. Most of the patients (75.7{\%}) were never-smokers. Adenocarcinoma was predominant (98.1{\%}), and two cases with pleomorphic carcinoma were identified. Sixty percent of patients had an extrathoracic metastatic lesion, and 22{\%} had an intracranial lesion at the initial presentation or at the time of recurrence. The median time to development of brain metastases was 12.0 months (range 2.1–84.1). The most common fusion partner was CD74 molecule gene (CD74), followed by syndecan 4 gene (SDC4), ezrin gene (EZR), tropomyosin 3 gene (TPM3), TRK-fused gene (TFG), zinc finger CCHC-type containing 8 gene (ZCCHC8), sacrolemma associated protein gene (SLMAP), and myosin VC gene (MYO5C). All of these fusion partners preserved the tyrosine kinase domain of ROS1. The median overall survival time was 52.1 months (95{\%} confidence interval [CI]: 23.6–not reached). In the 90 patients who were treated with pemetrexed-based chemotherapy, the overall response rate and progression-free survival time were 53.3{\%} and 8.0 months (95{\%} CI: 6.4–11.7), respectively. The overall response rate and progression-free survival time were 70.7{\%} and 12.7 months (95{\%} CI: 8.1–21.8), respectively, for the 50 patients treated with TKIs. Brain metastasis was more often observed during TKI treatment (15.5{\%}) than during pemetrexed-based chemotherapy (6.7{\%}). Conclusions: ROS1-positive NSCLC has distinct clinical characteristics, with an effective and durable response to both TKIs and pemetrexed-based chemotherapies. Regardless, given its novel characteristics and distinct clinical responses to conventional chemotherapies and TKIs, the treatment strategy for ROS1-positive NSCLC remains to be further developed.",
author = "Sehhoon Park and Ahn, {Beung Chul} and Lim, {Sung Won} and Sun, {Jong Mu} and Kim, {Hye Ryun} and Hong, {Min Hee} and Lee, {Se Hoon} and Ahn, {Jin Seok} and Keunchil Park and Choi, {Yoon La} and ByoungChul Cho and Ahn, {Myung Ju}",
year = "2018",
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doi = "10.1016/j.jtho.2018.05.026",
language = "English",
volume = "13",
pages = "1373--1382",
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}

Park, S, Ahn, BC, Lim, SW, Sun, JM, Kim, HR, Hong, MH, Lee, SH, Ahn, JS, Park, K, Choi, YL, Cho, B & Ahn, MJ 2018, 'Characteristics and Outcome of ROS1-Positive Non–Small Cell Lung Cancer Patients in Routine Clinical Practice', Journal of Thoracic Oncology, vol. 13, no. 9, pp. 1373-1382. https://doi.org/10.1016/j.jtho.2018.05.026

Characteristics and Outcome of ROS1-Positive Non–Small Cell Lung Cancer Patients in Routine Clinical Practice. / Park, Sehhoon; Ahn, Beung Chul; Lim, Sung Won; Sun, Jong Mu; Kim, Hye Ryun; Hong, Min Hee; Lee, Se Hoon; Ahn, Jin Seok; Park, Keunchil; Choi, Yoon La; Cho, ByoungChul; Ahn, Myung Ju.

In: Journal of Thoracic Oncology, Vol. 13, No. 9, 01.09.2018, p. 1373-1382.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Characteristics and Outcome of ROS1-Positive Non–Small Cell Lung Cancer Patients in Routine Clinical Practice

AU - Park, Sehhoon

AU - Ahn, Beung Chul

AU - Lim, Sung Won

AU - Sun, Jong Mu

AU - Kim, Hye Ryun

AU - Hong, Min Hee

AU - Lee, Se Hoon

AU - Ahn, Jin Seok

AU - Park, Keunchil

AU - Choi, Yoon La

AU - Cho, ByoungChul

AU - Ahn, Myung Ju

PY - 2018/9/1

Y1 - 2018/9/1

N2 - Introduction: ROS1-rearranged NSCLC is classified as a distinct molecular subset of NSCLC with a therapeutic target. ROS1 rearrangement is most often identified in never-smokers with adenocarcinoma and EGFR and ALK receptor tyrosine kinase gene (ALK) wild type. Treatment with tyrosine kinase inhibitors (TKIs), which target the ROS1 kinase domain, is considered the standard of care. TKIs have been shown to have a robust and durable response. However, information regarding the clinical outcomes of TKI treatment, including brain metastasis, remains limited. Methods: We identified 103 consecutive cases of ROS1-positive NSCLC by using break-apart fluorescence in situ hybridization (n = 84), next-generation sequencing (n = 23), or both (n = 3). Information regarding fusion breakpoints was available for eight patients. Clinical data, including patient characteristics, incidence of brain metastasis, response to chemotherapy, or to TKIs, were retrospectively analyzed. Results: The median patient age was 56 years, and 58.9% of the patients were female. Most of the patients (75.7%) were never-smokers. Adenocarcinoma was predominant (98.1%), and two cases with pleomorphic carcinoma were identified. Sixty percent of patients had an extrathoracic metastatic lesion, and 22% had an intracranial lesion at the initial presentation or at the time of recurrence. The median time to development of brain metastases was 12.0 months (range 2.1–84.1). The most common fusion partner was CD74 molecule gene (CD74), followed by syndecan 4 gene (SDC4), ezrin gene (EZR), tropomyosin 3 gene (TPM3), TRK-fused gene (TFG), zinc finger CCHC-type containing 8 gene (ZCCHC8), sacrolemma associated protein gene (SLMAP), and myosin VC gene (MYO5C). All of these fusion partners preserved the tyrosine kinase domain of ROS1. The median overall survival time was 52.1 months (95% confidence interval [CI]: 23.6–not reached). In the 90 patients who were treated with pemetrexed-based chemotherapy, the overall response rate and progression-free survival time were 53.3% and 8.0 months (95% CI: 6.4–11.7), respectively. The overall response rate and progression-free survival time were 70.7% and 12.7 months (95% CI: 8.1–21.8), respectively, for the 50 patients treated with TKIs. Brain metastasis was more often observed during TKI treatment (15.5%) than during pemetrexed-based chemotherapy (6.7%). Conclusions: ROS1-positive NSCLC has distinct clinical characteristics, with an effective and durable response to both TKIs and pemetrexed-based chemotherapies. Regardless, given its novel characteristics and distinct clinical responses to conventional chemotherapies and TKIs, the treatment strategy for ROS1-positive NSCLC remains to be further developed.

AB - Introduction: ROS1-rearranged NSCLC is classified as a distinct molecular subset of NSCLC with a therapeutic target. ROS1 rearrangement is most often identified in never-smokers with adenocarcinoma and EGFR and ALK receptor tyrosine kinase gene (ALK) wild type. Treatment with tyrosine kinase inhibitors (TKIs), which target the ROS1 kinase domain, is considered the standard of care. TKIs have been shown to have a robust and durable response. However, information regarding the clinical outcomes of TKI treatment, including brain metastasis, remains limited. Methods: We identified 103 consecutive cases of ROS1-positive NSCLC by using break-apart fluorescence in situ hybridization (n = 84), next-generation sequencing (n = 23), or both (n = 3). Information regarding fusion breakpoints was available for eight patients. Clinical data, including patient characteristics, incidence of brain metastasis, response to chemotherapy, or to TKIs, were retrospectively analyzed. Results: The median patient age was 56 years, and 58.9% of the patients were female. Most of the patients (75.7%) were never-smokers. Adenocarcinoma was predominant (98.1%), and two cases with pleomorphic carcinoma were identified. Sixty percent of patients had an extrathoracic metastatic lesion, and 22% had an intracranial lesion at the initial presentation or at the time of recurrence. The median time to development of brain metastases was 12.0 months (range 2.1–84.1). The most common fusion partner was CD74 molecule gene (CD74), followed by syndecan 4 gene (SDC4), ezrin gene (EZR), tropomyosin 3 gene (TPM3), TRK-fused gene (TFG), zinc finger CCHC-type containing 8 gene (ZCCHC8), sacrolemma associated protein gene (SLMAP), and myosin VC gene (MYO5C). All of these fusion partners preserved the tyrosine kinase domain of ROS1. The median overall survival time was 52.1 months (95% confidence interval [CI]: 23.6–not reached). In the 90 patients who were treated with pemetrexed-based chemotherapy, the overall response rate and progression-free survival time were 53.3% and 8.0 months (95% CI: 6.4–11.7), respectively. The overall response rate and progression-free survival time were 70.7% and 12.7 months (95% CI: 8.1–21.8), respectively, for the 50 patients treated with TKIs. Brain metastasis was more often observed during TKI treatment (15.5%) than during pemetrexed-based chemotherapy (6.7%). Conclusions: ROS1-positive NSCLC has distinct clinical characteristics, with an effective and durable response to both TKIs and pemetrexed-based chemotherapies. Regardless, given its novel characteristics and distinct clinical responses to conventional chemotherapies and TKIs, the treatment strategy for ROS1-positive NSCLC remains to be further developed.

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