title: Reduction in Hepatocyte Growth Factor Serum Levels is Associated with Improved Prognosis in Advanced Lung Adenocarcinoma Patients Treated with Afatinib: a Phase II Trial.
abstract: C-met and its ligand, hepatocyte growth factor (HGF) have been associated with the resistance mechanism of EGFR-TKIs. HGF was evaluated as a clinical-marker of response in NSCLC patients treated with afatinib.
  
  
  
  Sixty-six patients with stage IIIB/IV lung adenocarcinoma and progression to any-line chemotherapy received afatinib 40 mg/day. Mutational EGFR and HER2 status were assessed by RT-PCR. HER2 amplification was evaluated by FISH. Serum HGF content was measured by ELISA before and 2 months after the start of treatment. HGF levels were assessed with the objective response rate (ORR), progression-free-survival (PFS), and overall survival (OS). This trial was registered on ClinicalTrials.gov: NCT01542437.
  
  
  
  Fifty patients (75 %) were EGFR mutation positive. Response was achieved in 59 % of all patients and 78 % of EGFR mutated patients. Median PFS was 10 [95 % CI 6.8-13.1] and 14.5 months [10.9-18.9] for all and EGFR mutated patients, respectively. Median OS was 22.8 [17.5-28.1] and 32.4 months [18.3-46.6] for all and EGFR mutated patients, respectively. Patients with reduced serum HGF levels had improved ORR (75 % vs 44 %; p = 0.011), PFS (15.1 [2.9-27.3] vs 6.5 months [3.9-9.1]; p = 0.005) and OS (NR vs 14.5 months [7.8 - 21.3] p = 0.007). A reduction in serum HGF levels was an independent factor associated with longer PFS (HR 0.40; p = 0.021) and OS (HR 0.31; p = 0.006) in all and EGFR mutated patients.
  
  
  
  A reduction in serum HGF levels was associated with improved outcomes in patients treated with afatinib. These results suggest HGF might have a role as a mechanism of resistance to EGFR-TKIs. HGF could represent a potential therapeutic target to prevent or reverse resistance particularly in EGFR mutated patients.
authors.affiliation: Thoracic Oncology Unit, Instituto Nacional de Cancerología de México (INCan), Av. San Fernando No. 22, Col. Sección XVI, Tlalpan, CP 14080, Mexico City, Mexico. ogar@unam.mx.|Experimental Oncology Laboratory, INCan, Av. San Fernando No. 22, Col. Sección XVI, Delegación Tlalpan, CP 14080, Mexico City, Mexico. ogar@unam.mx.
authors.forename: Oscar
authors.initials: O
authors.lastname: Arrieta
authors.affiliation: Experimental Oncology Laboratory, INCan, Av. San Fernando No. 22, Col. Sección XVI, Delegación Tlalpan, CP 14080, Mexico City, Mexico.
authors.forename: Graciela
authors.initials: G
authors.lastname: Cruz-Rico
authors.affiliation: Cancer Care in the Elderly Clinic, Department of Geriatrics, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Av. Vasco de Quiroga No. 15, Col. Sección XVI, Tlalpan, CP 14080, Mexico City, Mexico.
authors.forename: Enrique
authors.initials: E
authors.lastname: Soto-Perez-de-Celis
authors.affiliation: Experimental Oncology Laboratory, INCan, Av. San Fernando No. 22, Col. Sección XVI, Delegación Tlalpan, CP 14080, Mexico City, Mexico.
authors.forename: Laura-Alejandra
authors.initials: LA
authors.lastname: Ramírez-Tirado
authors.affiliation: Thoracic Oncology Unit, Instituto Nacional de Cancerología de México (INCan), Av. San Fernando No. 22, Col. Sección XVI, Tlalpan, CP 14080, Mexico City, Mexico.
authors.forename: Enrique
authors.initials: E
authors.lastname: Caballe-Perez
authors.affiliation: Thoracic Oncology Unit, Instituto Nacional de Cancerología de México (INCan), Av. San Fernando No. 22, Col. Sección XVI, Tlalpan, CP 14080, Mexico City, Mexico.
authors.forename: Jorge-Negueb
authors.initials: JN
authors.lastname: Martínez-Hernández
authors.affiliation: Thoracic Oncology Unit, Instituto Nacional de Cancerología de México (INCan), Av. San Fernando No. 22, Col. Sección XVI, Tlalpan, CP 14080, Mexico City, Mexico.
authors.forename: Ivan
authors.initials: I
authors.lastname: Martinez-Alvarez
authors.affiliation: Experimental Oncology Laboratory, INCan, Av. San Fernando No. 22, Col. Sección XVI, Delegación Tlalpan, CP 14080, Mexico City, Mexico.
authors.forename: Giovanny
authors.initials: G
authors.lastname: Soca-Chafre
authors.affiliation: Thoracic Oncology Unit, Instituto Nacional de Cancerología de México (INCan), Av. San Fernando No. 22, Col. Sección XVI, Tlalpan, CP 14080, Mexico City, Mexico.
authors.forename: Eleazar Omar
authors.initials: EO
authors.lastname: Macedo-Pérez
authors.affiliation: Laboratory of Translational Cancer Research and Cellular Therapy, Oncology Hospital, Medical Center Siglo XXI, Mexican Institute of Social Security (IMSS), CP 06720, Mexico City, Mexico.
authors.forename: Horacio
authors.initials: H
authors.lastname: Astudillo-de la Vega
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy*; D000077192:Adenocarcinoma of Lung; D000077716:Afatinib; D018572:Disease-Free Survival; D005260:Female; D017228:Hepatocyte Growth Factor / Q000097:blood*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D000077716:Afatinib; D017228:Hepatocyte Growth Factor