title: Bevacizumab, Pemetrexed, and Cisplatin, or Bevacizumab and Erlotinib for Patients With Advanced Non-Small-Cell Lung Cancer Stratified by Epidermal Growth Factor Receptor Mutation: Phase II Trial SAKK19/09.
abstract: OBJECTIVE
  The goal was to demonstrate that tailored therapy, according to tumor histology and epidermal growth factor receptor (EGFR) mutation status, and the introduction of novel drug combinations in the treatment of advanced non-small-cell lung cancer are promising for further investigation.
  
  
  METHODS
  We conducted a multicenter phase II trial with mandatory EGFR testing and 2 strata. Patients with EGFR wild type received 4 cycles of bevacizumab, pemetrexed, and cisplatin, followed by maintenance with bevacizumab and pemetrexed until progression. Patients with EGFR mutations received bevacizumab and erlotinib until progression. Patients had computed tomography scans every 6 weeks and repeat biopsy at progression. The primary end point was progression-free survival (PFS) ≥ 35% at 6 months in stratum EGFR wild type; 77 patients were required to reach a power of 90% with an alpha of 5%. Secondary end points were median PFS, overall survival, best overall response rate (ORR), and tolerability. Further biomarkers and biopsy at progression were also evaluated.
  
  
  RESULTS
  A total of 77 evaluable patients with EGFR wild type received an average of 9 cycles (range, 1-25). PFS at 6 months was 45.5%, median PFS was 6.9 months, overall survival was 12.1 months, and ORR was 62%. Kirsten rat sarcoma oncogene mutations and circulating vascular endothelial growth factor negatively correlated with survival, but thymidylate synthase expression did not. A total of 20 patients with EGFR mutations received an average of 16 cycles. PFS at 6 months was 70%, median PFS was 14 months, and ORR was 70%. Biopsy at progression was safe and successful in 71% of the cases.
  
  
  CONCLUSIONS
  Both combination therapies were promising for further studies. Biopsy at progression was feasible and will be part of future SAKK studies to investigate molecular mechanisms of resistance.
authors.affiliation: Medical Oncology, Cantonal Hospital Luzern, Luzern, Switzerland. Electronic address: oliver.gautschi@luks.ch.
authors.forename: Oliver
authors.initials: O
authors.lastname: Gautschi
authors.affiliation: Clinical Research Unit of the Dr. Dubois-Ferrière Dinu Lipatti Foundation, Oncology Center, Geneva University Hospital, Geneva, Switzerland.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Mach
authors.affiliation: Medical Oncology, University Hospital Basel, Basel, Switzerland.
authors.forename: Sacha I
authors.initials: SI
authors.lastname: Rothschild
authors.affiliation: SAKK Coordinating Center, Bern, Switzerland.
authors.forename: Qiyu
authors.initials: Q
authors.lastname: Li
authors.affiliation: Medical Oncology, University Hospital Zurich, Zurich, Switzerland.
authors.forename: Rolf A
authors.initials: RA
authors.lastname: Stahel
authors.affiliation: Medical Oncology, University Hospital Basel, Basel, Switzerland.
authors.forename: Alfred
authors.initials: A
authors.lastname: Zippelius
authors.affiliation: Medical Oncology, Cantonal Hospital Graubünden, Chur, Switzerland.
authors.forename: Richard
authors.initials: R
authors.lastname: Cathomas
authors.affiliation: Medical Oncology, Cantonal Hospital St Gallen, St Gallen, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Früh
authors.affiliation: Medical Oncology, Cantonal Hospital Fribourg, Fribourg, Switzerland.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Betticher
authors.affiliation: Cancer Center, University Hospital Lausanne, Lausanne, Switzerland.
authors.forename: Solange
authors.initials: S
authors.lastname: Peters
authors.affiliation: Medical Oncology, Cantonal Hospital Thun, Thun, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rauch
authors.affiliation: Medical Oncology, Cantonal Hospital Valais, Sion, Switzerland.
authors.forename: Jonas
authors.initials: J
authors.lastname: Feilchenfeldt
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Bubendorf
authors.affiliation: Institute of Pathology, University Hospital Basel, Basel, Switzerland.
authors.forename: Spasenija
authors.initials: S
authors.lastname: Savic
authors.affiliation: Department of Clinical Research, University of Bern, Bern, Switzerland.
authors.forename: Rolf
authors.initials: R
authors.lastname: Jaggi
authors.affiliation: Department of Hematology, University Hospital Bern, Bern, Switzerland.
authors.forename: Elisabeth Oppliger
authors.initials: EO
authors.lastname: Leibundgut
authors.affiliation: Laboratory of Clinical Chemistry, University Hospital Bern, Bern, Switzerland.
authors.forename: Carlo
authors.initials: C
authors.lastname: Largiadèr
authors.affiliation: Pulmonology, Cantonal Hospital St Gallen, St Gallen, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Brutsche
authors.affiliation: SAKK Coordinating Center, Bern, Switzerland.
authors.forename: Christiane
authors.initials: C
authors.lastname: Pilop
authors.affiliation: SAKK Coordinating Center, Bern, Switzerland.
authors.forename: Lukas
authors.initials: L
authors.lastname: Stalder
authors.affiliation: Medical Oncology, Cantonal Hospital Winterthur, Winterthur, Switzerland.
authors.forename: Miklos
authors.initials: M
authors.lastname: Pless
authors.affiliation: Medical Oncology, University Hospital Bern, Bern, Switzerland.
authors.forename: Adrian F
authors.initials: AF
authors.lastname: Ochsenbein
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D001706:Biopsy; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000068437:Pemetrexed / Q000008:administration & dosage; D015996:Survival Rate
chemical_list: D000068437:Pemetrexed; D000068258:Bevacizumab; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D002945:Cisplatin
keywords: Bevacizumab; Chemotherapy; Erlotinib; Lung cancer; Pemetrexed