Glenwood D Goss1, Enriqueta Felip2, Manuel Cobo3, Shun Lu4, Konstantinos Syrigos5, Ki Hyeong Lee6, Erdem Göker7, Vassilis Georgoulias8, Wei Li9, Salih Guclu10, Dolores Isla11, Young Joo Min12, Alessandro Morabito13, Andrea Ardizzoni14, Shirish M Gadgeel15, Andrea Fülöp16, Claudia Bühnemann17, Neil Gibson17, Nicole Krämer18, Flavio Solca19, Agnieszka Cseh19, Eva Ehrnrooth20, Jean-Charles Soria21. 1. Division of Medical Oncology, The Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada. 2. Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain. 3. Department of Medical Oncology, Hospital Universitario Málaga General, Instituto de Investigación Biomédica de Málaga, Málaga, Spain. 4. Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China. 5. Oncology Unit GPP, Athens School of Medicine, Athens, Greece. 6. Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, South Korea. 7. Ege University Faculty of Medicine, Izmir, Turkey. 8. Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Crete, Greece. 9. Cancer Center, First Hospital Affiliated to Jilin University, Jilin, China. 10. Chest Diseases Clinic, Izmir Chest Diseases Research Hospital, Izmir, Turkey. 11. Medical Oncology Department, University Hospital Lozano Blesa, Zaragoza, Spain. 12. Department of Medicine, Ulsan University Hospital, Ulsan, South Korea. 13. Medical Oncology Unit, Thoraco-Pulmonary Department, Istituto Nazionale Tumori-IRCCS-"Fondazione G. Pascale," Naples, Italy. 14. Division of Medical Oncology, Sant'Orsola-Malpighi University Hospital, Bologna, Italy. 15. Department of Oncology, Karmanos Cancer Institute/Wayne State University, Detroit, Michigan. 16. National Koranyi Institute, Budapest, Hungary. 17. Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. 18. Staburo GmbH, Munich, Germany, on behalf of Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany. 19. Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria. 20. Boehringer Ingelheim, Danmark A/S, Denmark. 21. Department of Medical Oncology, Gustave Roussy Cancer Campus and University Paris-Sud, Paris, France.
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 witherlotinib). 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.
RCT Entities:
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.
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