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Ref Type Journal Article
PMID (29902295)
Authors 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 JC
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.
Journal Vol Issue Date Pages Journal Short Title
JAMA oncology 2018 Jun 14 1189-1197 JAMA Oncol
URL
Abstract Text Treatment choice for lung squamous cell carcinoma could be aided by identifying predictive biomarkers.To assess whether patient outcomes in the LUX-Lung 8 trial were associated with ERBB gene family member aberrations in tumor specimens.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.Patients were randomized 1:1 to treatment with afatinib dimaleate (40 mg/d; n = 398) or erlotinib hydrochloride (150 mg/d; n = 397).Overall survival, PFS, pooled and individual ERBB gene mutations, ERBB copy number alterations, and EGFR expression.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.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.ClinicalTrials.gov Identifier: NCT01523587.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ERBB3 P1212S missense unknown ERBB3 (HER3) P1212S lies within the cytoplasmic domain of the Erbb3 (Her3) protein (UniProt.org). P1212S has been identified in the scientific literature (PMID: 26214590, PMID: 29338072, PMID: 29902295), but has not been biochemically characterized and therefore, its effect on Erbb3 (Her3) protein function is unknown (PubMed, Jan 2024).
ERBB3 R103H missense unknown ERBB3 (HER3) R103H lies within the extracellular domain of the Erbb3 (Her3) protein (UniProt.org). R103H has been identified in the scientific literature (PMID: 29902295), but has not been biochemically characterized and therefore, its effect on Erbb3 (Her3) protein function is unknown (PubMed, Mar 2024).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB4 mutant lung squamous cell carcinoma predicted - sensitive Afatinib Phase III Actionable In a Phase III trial (LUX-Lung 8), secondary analysis demonstrated favorable outcomes with Gilotrif (afatinib) treatment compared to Tarceva (erlotinib) in lung squamous cell carcinoma patients with ERBB (HER) family mutations, and ERBB4 (HER4) mutations predicted an OS (HR=0.22) and PFS (HR=0.21) benefit for Gilotrif (afatinib) over Tarceva (erlotinib) treatment (PMID: 29902295; NCT01523587). 29902295