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 Solca, Agnieszka Cseh, Eva Ehrnrooth, Jean-Charles Soria, 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 Solca, Agnieszka Cseh, Eva Ehrnrooth, Jean-Charles Soria
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.
Conflict of interest statement
Conflict of Interest Disclosures: Dr Goss reported participating on advisory boards for AstraZeneca, Boehringer Ingelheim, Pfizer, Eli Lilly and Company, Bristol-Myers Squibb Company, and Celgene. Dr Felip reported participating on advisory boards for Eli Lilly, Pfizer, Roche, Merck Sharp & Dohme Corp, and Boehringer Ingelheim and receiving lecture fees from AstraZeneca, Bristol-Myers Squibb Company, and Novartis. Dr Morabito reported receiving honoraria from Roche, AstraZeneca, Boehringer Ingelheim, Bayer, and Pfizer. Dr Ardizzoni reported participating on advisory boards and receiving honoraria from Bristol-Myers Squibb Company, Merck Sharp & Dohme Corp, Eli Lilly and Company, and Boehringer Ingelheim and receiving honoraria from Pfizer and Bayer. Dr Gadgeel reported participating on advisory boards for Boehringer Ingelheim, Pfizer, Genentech, Ariad Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb Company, and Roche. Drs Gibson, Krämer, Solca, Cseh, and Ehrnrooth are employees of Boehringer Ingelheim. Dr Soria reported receiving honoraria from AstraZeneca, Astex, Covagen, Clovis Oncology, GlaxoSmithKline, Gammamabs Pharma, Eli Lilly and Company, Merck Sharp & Dohme Corp, Mission Therapeutics, Merus, Pfizer, Pierre Fabre Laboratories, Roche-Genentech, Sanofi, Servier, and Takeda. No other disclosures were reported.
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Source: PubMed