Association of ERBB Mutations With Clinical Outcomes of Afatinib- or Erlotinib-Treated Patients With Lung Squamous Cell Carcinoma: Secondary Analysis of the LUX-Lung 8 Randomized Clinical Trial

Glenwood D Goss, Enriqueta Felip, Manuel Cobo, Shun Lu, Konstantinos Syrigos, Ki Hyeong Lee, Erdem Göker, Vassilis Georgoulias, Wei Li, Salih Guclu, Dolores Isla, Young Joo Min, Alessandro Morabito, Andrea Ardizzoni, Shirish M Gadgeel, Andrea Fülöp, Claudia Bühnemann, Neil Gibson, Nicole Krämer, Flavio SolcaAgnieszka Cseh, Eva Ehrnrooth, Jean-Charles Soria

Research output: Contribution to journalArticle

Abstract

Importance: Treatment choice for lung squamous cell carcinoma could be aided by identifying predictive biomarkers.

Objective: To assess whether patient outcomes in the LUX-Lung 8 trial were associated with ERBB gene family member aberrations in tumor specimens.

Design, Setting, and Participants: Ad hoc secondary analysis of the LUX-Lung 8 trial conducted at 183 centers in 23 countries from March 30, 2012, to January 30, 2014. Eligible patients had stage IIIB or IV lung squamous cell carcinoma with progressive disease after 4 or more cycles of platinum-based chemotherapy. Tumor genetic analysis (TGA) was performed using next-generation sequencing in a cohort enriched for patients with progression-free survival (PFS) of more than 2 months. Epidermal growth factor receptor (EGFR) expression levels were assessed by immunohistochemistry in a separate cohort of patients from the LUX-Lung 8 population. Associations of PFS and overall survival (OS) with ERBB gene alterations and EGFR expression levels were assessed. This analysis was conducted from February 26, 2015, to June 12, 2017.

Interventions: Patients were randomized 1:1 to treatment with afatinib dimaleate (40 mg/d; n = 398) or erlotinib hydrochloride (150 mg/d; n = 397).

Main Outcomes and Measures: Overall survival, PFS, pooled and individual ERBB gene mutations, ERBB copy number alterations, and EGFR expression.

Results: Tumor specimens from 245 patients were eligible for next-generation sequencing (TGA subset: 132 patients treated with afatinib; 113 patients treated with erlotinib). In this population, outcomes were improved with afatinib vs erlotinib treatment (PFS: median, 3.5 vs 2.5 months; hazard ratio [HR], 0.69; 95% CI, 0.51-0.92; P = .01; OS: median, 8.4 vs 6.6 months; HR, 0.81; 95% CI, 0.62-1.05; P = .12). Of 245 patients in the TGA subset, 53 (21.6%) had tumors with 1 or more ERBB mutations. Among afatinib-treated patients, PFS (median, 4.9 vs 3.0 months; HR, 0.62; 95% CI, 0.37-1.02; P = .06) and OS (median, 10.6 vs 8.1 months; HR, 0.75; 95% CI, 0.47-1.17; P = .21) were longer among those with ERBB mutation-positive disease than among those without. The presence of HER2 mutations was associated with favorable PFS and OS following afatinib vs erlotinib treatment. There was no apparent association between copy number alteration or EGFR expression level and outcome.

Conclusions and Relevance: Next-generation sequencing may help identify patients with lung squamous cell carcinoma who would derive additional benefit from treatment with afatinib. The role of ERBB mutations, particularly HER2 mutations, as predictive biomarkers for afatinib treatment in this setting warrants further evaluation.

Trial Registration: ClinicalTrials.gov Identifier: NCT01523587.

Original languageEnglish
JournalJAMA oncology
DOIs
Publication statusPublished - 2018

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Squamous Cell Carcinoma
Randomized Controlled Trials
Lung
Mutation
Disease-Free Survival
Survival
Epidermal Growth Factor Receptor
Neoplasms
BIBW 2992
Erlotinib Hydrochloride
Therapeutics
Biomarkers
erbB-1 Genes
Platinum
Population
Genes
Immunohistochemistry
Outcome Assessment (Health Care)
Drug Therapy

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Association of ERBB Mutations With Clinical Outcomes of Afatinib- or Erlotinib-Treated Patients With Lung Squamous Cell Carcinoma : Secondary Analysis of the LUX-Lung 8 Randomized Clinical Trial. / Goss, Glenwood D; Felip, Enriqueta; Cobo, Manuel; Lu, Shun; Syrigos, Konstantinos; Lee, Ki Hyeong; Göker, Erdem; Georgoulias, Vassilis; Li, Wei; Guclu, Salih; Isla, Dolores; Min, Young Joo; Morabito, Alessandro; Ardizzoni, Andrea; Gadgeel, Shirish M; Fülöp, Andrea; Bühnemann, Claudia; Gibson, Neil; Krämer, Nicole; Solca, Flavio; Cseh, Agnieszka; Ehrnrooth, Eva; Soria, Jean-Charles.

In: JAMA oncology, 2018.

Research output: Contribution to journalArticle

Goss, GD, Felip, E, Cobo, M, Lu, S, Syrigos, K, Lee, KH, Göker, E, Georgoulias, V, Li, W, Guclu, S, Isla, D, Min, YJ, Morabito, A, Ardizzoni, A, Gadgeel, SM, Fülöp, A, Bühnemann, C, Gibson, N, Krämer, N, Solca, F, Cseh, A, Ehrnrooth, E & Soria, J-C 2018, 'Association of ERBB Mutations With Clinical Outcomes of Afatinib- or Erlotinib-Treated Patients With Lung Squamous Cell Carcinoma: Secondary Analysis of the LUX-Lung 8 Randomized Clinical Trial', JAMA oncology. https://doi.org/10.1001/jamaoncol.2018.0775
Goss, Glenwood D ; Felip, Enriqueta ; Cobo, Manuel ; Lu, Shun ; Syrigos, Konstantinos ; Lee, Ki Hyeong ; Göker, Erdem ; Georgoulias, Vassilis ; Li, Wei ; Guclu, Salih ; Isla, Dolores ; Min, Young Joo ; Morabito, Alessandro ; Ardizzoni, Andrea ; Gadgeel, Shirish M ; Fülöp, Andrea ; Bühnemann, Claudia ; Gibson, Neil ; Krämer, Nicole ; Solca, Flavio ; Cseh, Agnieszka ; Ehrnrooth, Eva ; Soria, Jean-Charles. / Association of ERBB Mutations With Clinical Outcomes of Afatinib- or Erlotinib-Treated Patients With Lung Squamous Cell Carcinoma : Secondary Analysis of the LUX-Lung 8 Randomized Clinical Trial. In: JAMA oncology. 2018.
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title = "Association of ERBB Mutations With Clinical Outcomes of Afatinib- or Erlotinib-Treated Patients With Lung Squamous Cell Carcinoma: Secondary Analysis of the LUX-Lung 8 Randomized Clinical Trial",
abstract = "Importance: Treatment choice for lung squamous cell carcinoma could be aided by identifying predictive biomarkers.Objective: To assess whether patient outcomes in the LUX-Lung 8 trial were associated with ERBB gene family member aberrations in tumor specimens.Design, Setting, and Participants: Ad hoc secondary analysis of the LUX-Lung 8 trial conducted at 183 centers in 23 countries from March 30, 2012, to January 30, 2014. Eligible patients had stage IIIB or IV lung squamous cell carcinoma with progressive disease after 4 or more cycles of platinum-based chemotherapy. Tumor genetic analysis (TGA) was performed using next-generation sequencing in a cohort enriched for patients with progression-free survival (PFS) of more than 2 months. Epidermal growth factor receptor (EGFR) expression levels were assessed by immunohistochemistry in a separate cohort of patients from the LUX-Lung 8 population. Associations of PFS and overall survival (OS) with ERBB gene alterations and EGFR expression levels were assessed. This analysis was conducted from February 26, 2015, to June 12, 2017.Interventions: Patients were randomized 1:1 to treatment with afatinib dimaleate (40 mg/d; n = 398) or erlotinib hydrochloride (150 mg/d; n = 397).Main Outcomes and Measures: Overall survival, PFS, pooled and individual ERBB gene mutations, ERBB copy number alterations, and EGFR expression.Results: Tumor specimens from 245 patients were eligible for next-generation sequencing (TGA subset: 132 patients treated with afatinib; 113 patients treated with erlotinib). In this population, outcomes were improved with afatinib vs erlotinib treatment (PFS: median, 3.5 vs 2.5 months; hazard ratio [HR], 0.69; 95{\%} CI, 0.51-0.92; P = .01; OS: median, 8.4 vs 6.6 months; HR, 0.81; 95{\%} CI, 0.62-1.05; P = .12). Of 245 patients in the TGA subset, 53 (21.6{\%}) had tumors with 1 or more ERBB mutations. Among afatinib-treated patients, PFS (median, 4.9 vs 3.0 months; HR, 0.62; 95{\%} CI, 0.37-1.02; P = .06) and OS (median, 10.6 vs 8.1 months; HR, 0.75; 95{\%} CI, 0.47-1.17; P = .21) were longer among those with ERBB mutation-positive disease than among those without. The presence of HER2 mutations was associated with favorable PFS and OS following afatinib vs erlotinib treatment. There was no apparent association between copy number alteration or EGFR expression level and outcome.Conclusions and Relevance: Next-generation sequencing may help identify patients with lung squamous cell carcinoma who would derive additional benefit from treatment with afatinib. The role of ERBB mutations, particularly HER2 mutations, as predictive biomarkers for afatinib treatment in this setting warrants further evaluation.Trial Registration: ClinicalTrials.gov Identifier: NCT01523587.",
author = "Goss, {Glenwood D} and Enriqueta Felip and Manuel Cobo and Shun Lu and Konstantinos Syrigos and Lee, {Ki Hyeong} and Erdem G{\"o}ker and Vassilis Georgoulias and Wei Li and Salih Guclu and Dolores Isla and Min, {Young Joo} and Alessandro Morabito and Andrea Ardizzoni and Gadgeel, {Shirish M} and Andrea F{\"u}l{\"o}p and Claudia B{\"u}hnemann and Neil Gibson and Nicole Kr{\"a}mer and Flavio Solca and Agnieszka Cseh and Eva Ehrnrooth and Jean-Charles Soria",
year = "2018",
doi = "10.1001/jamaoncol.2018.0775",
language = "English",
journal = "JAMA oncology",
issn = "2374-2437",
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TY - JOUR

T1 - Association of ERBB Mutations With Clinical Outcomes of Afatinib- or Erlotinib-Treated Patients With Lung Squamous Cell Carcinoma

T2 - Secondary Analysis of the LUX-Lung 8 Randomized Clinical Trial

AU - Goss, Glenwood D

AU - Felip, Enriqueta

AU - Cobo, Manuel

AU - Lu, Shun

AU - Syrigos, Konstantinos

AU - Lee, Ki Hyeong

AU - Göker, Erdem

AU - Georgoulias, Vassilis

AU - Li, Wei

AU - Guclu, Salih

AU - Isla, Dolores

AU - Min, Young Joo

AU - Morabito, Alessandro

AU - Ardizzoni, Andrea

AU - Gadgeel, Shirish M

AU - Fülöp, Andrea

AU - Bühnemann, Claudia

AU - Gibson, Neil

AU - Krämer, Nicole

AU - Solca, Flavio

AU - Cseh, Agnieszka

AU - Ehrnrooth, Eva

AU - Soria, Jean-Charles

PY - 2018

Y1 - 2018

N2 - Importance: Treatment choice for lung squamous cell carcinoma could be aided by identifying predictive biomarkers.Objective: To assess whether patient outcomes in the LUX-Lung 8 trial were associated with ERBB gene family member aberrations in tumor specimens.Design, Setting, and Participants: Ad hoc secondary analysis of the LUX-Lung 8 trial conducted at 183 centers in 23 countries from March 30, 2012, to January 30, 2014. Eligible patients had stage IIIB or IV lung squamous cell carcinoma with progressive disease after 4 or more cycles of platinum-based chemotherapy. Tumor genetic analysis (TGA) was performed using next-generation sequencing in a cohort enriched for patients with progression-free survival (PFS) of more than 2 months. Epidermal growth factor receptor (EGFR) expression levels were assessed by immunohistochemistry in a separate cohort of patients from the LUX-Lung 8 population. Associations of PFS and overall survival (OS) with ERBB gene alterations and EGFR expression levels were assessed. This analysis was conducted from February 26, 2015, to June 12, 2017.Interventions: Patients were randomized 1:1 to treatment with afatinib dimaleate (40 mg/d; n = 398) or erlotinib hydrochloride (150 mg/d; n = 397).Main Outcomes and Measures: Overall survival, PFS, pooled and individual ERBB gene mutations, ERBB copy number alterations, and EGFR expression.Results: Tumor specimens from 245 patients were eligible for next-generation sequencing (TGA subset: 132 patients treated with afatinib; 113 patients treated with erlotinib). In this population, outcomes were improved with afatinib vs erlotinib treatment (PFS: median, 3.5 vs 2.5 months; hazard ratio [HR], 0.69; 95% CI, 0.51-0.92; P = .01; OS: median, 8.4 vs 6.6 months; HR, 0.81; 95% CI, 0.62-1.05; P = .12). Of 245 patients in the TGA subset, 53 (21.6%) had tumors with 1 or more ERBB mutations. Among afatinib-treated patients, PFS (median, 4.9 vs 3.0 months; HR, 0.62; 95% CI, 0.37-1.02; P = .06) and OS (median, 10.6 vs 8.1 months; HR, 0.75; 95% CI, 0.47-1.17; P = .21) were longer among those with ERBB mutation-positive disease than among those without. The presence of HER2 mutations was associated with favorable PFS and OS following afatinib vs erlotinib treatment. There was no apparent association between copy number alteration or EGFR expression level and outcome.Conclusions and Relevance: Next-generation sequencing may help identify patients with lung squamous cell carcinoma who would derive additional benefit from treatment with afatinib. The role of ERBB mutations, particularly HER2 mutations, as predictive biomarkers for afatinib treatment in this setting warrants further evaluation.Trial Registration: ClinicalTrials.gov Identifier: NCT01523587.

AB - Importance: Treatment choice for lung squamous cell carcinoma could be aided by identifying predictive biomarkers.Objective: To assess whether patient outcomes in the LUX-Lung 8 trial were associated with ERBB gene family member aberrations in tumor specimens.Design, Setting, and Participants: Ad hoc secondary analysis of the LUX-Lung 8 trial conducted at 183 centers in 23 countries from March 30, 2012, to January 30, 2014. Eligible patients had stage IIIB or IV lung squamous cell carcinoma with progressive disease after 4 or more cycles of platinum-based chemotherapy. Tumor genetic analysis (TGA) was performed using next-generation sequencing in a cohort enriched for patients with progression-free survival (PFS) of more than 2 months. Epidermal growth factor receptor (EGFR) expression levels were assessed by immunohistochemistry in a separate cohort of patients from the LUX-Lung 8 population. Associations of PFS and overall survival (OS) with ERBB gene alterations and EGFR expression levels were assessed. This analysis was conducted from February 26, 2015, to June 12, 2017.Interventions: Patients were randomized 1:1 to treatment with afatinib dimaleate (40 mg/d; n = 398) or erlotinib hydrochloride (150 mg/d; n = 397).Main Outcomes and Measures: Overall survival, PFS, pooled and individual ERBB gene mutations, ERBB copy number alterations, and EGFR expression.Results: Tumor specimens from 245 patients were eligible for next-generation sequencing (TGA subset: 132 patients treated with afatinib; 113 patients treated with erlotinib). In this population, outcomes were improved with afatinib vs erlotinib treatment (PFS: median, 3.5 vs 2.5 months; hazard ratio [HR], 0.69; 95% CI, 0.51-0.92; P = .01; OS: median, 8.4 vs 6.6 months; HR, 0.81; 95% CI, 0.62-1.05; P = .12). Of 245 patients in the TGA subset, 53 (21.6%) had tumors with 1 or more ERBB mutations. Among afatinib-treated patients, PFS (median, 4.9 vs 3.0 months; HR, 0.62; 95% CI, 0.37-1.02; P = .06) and OS (median, 10.6 vs 8.1 months; HR, 0.75; 95% CI, 0.47-1.17; P = .21) were longer among those with ERBB mutation-positive disease than among those without. The presence of HER2 mutations was associated with favorable PFS and OS following afatinib vs erlotinib treatment. There was no apparent association between copy number alteration or EGFR expression level and outcome.Conclusions and Relevance: Next-generation sequencing may help identify patients with lung squamous cell carcinoma who would derive additional benefit from treatment with afatinib. The role of ERBB mutations, particularly HER2 mutations, as predictive biomarkers for afatinib treatment in this setting warrants further evaluation.Trial Registration: ClinicalTrials.gov Identifier: NCT01523587.

U2 - 10.1001/jamaoncol.2018.0775

DO - 10.1001/jamaoncol.2018.0775

M3 - Article

C2 - 29902295

JO - JAMA oncology

JF - JAMA oncology

SN - 2374-2437

ER -