A phase 3 trial of empiric chemotherapy with cisplatin and gemcitabine or systemic treatment tailored by molecular gene expression analysis in pati...

Date 28 September 2019
Event ESMO 2019 Congress
Session Proffered Paper – Translational research
Topics Carcinoma of Unknown Primary Site (CUP)
Presenter Karim Fizazi
Citation Annals of Oncology (2019) 30 (suppl_5): v851-v934. 10.1093/annonc/mdz394
Authors K. Fizazi1, A. Maillard2, N. Penel3, G. Baciarello1, D. Allouache4, G. Daugaard5, A. Van de Wouw6, G. Soler7, E. Vauleon8, L. Chaigneau9, R. Jansen10, F. Losa Gaspa11, R. Morales Barrera12, C. Balana13, D. Tosi14, B. Chauffert15, C.A. Schnabel16, G. Martineau17, S. Culine18, I. Borget19
  • 1Cancer Medicine, Gustave Roussy, 94805 - Villejuif/FR
  • 2Biostatistics, Gustave Roussy, 94805 - Villejuif/FR
  • 3General Oncology Department, Centre Oscar Lambret, 59020 - Lille/FR
  • 4Medical Oncology, Centre Francois Baclesse, Caen/FR
  • 5Medical Oncology, Rigshospitalet, Copenhagen University Hospital, 2100 - Copenhagen/DK
  • 6Medical Oncology, Medisch Centrum voor Noord-Limburg, Venlo/NL
  • 7Medical Oncology, Institut Català d´Oncologia, Barcelona/ES
  • 8Medical Oncology, Centre Eugene - Marquis, 35042 - Rennes/FR
  • 9Medical Oncology, CHRU Jean Minjoz, Besançon/FR
  • 10Medical Oncology, Maastricht University Medical Center, Maastricht/NL
  • 11Medical Oncology, Hospital Moises Broggi, Barcelona/ES
  • 12Medical Oncology Dept., Vall d'Hebron University Hospital, 08035 - Barcelona/ES
  • 13Medical Oncology, Germans Trias i Pujol, Barcelona/ES
  • 14Medical Oncology, ICM Regional Cancer Institute of Montpellier, 34090 - Montpellier/FR
  • 15Medical Oncology, CHU Amiens, Amiens-Picardie/FR
  • 16Biology, bioTheranostics, Inc., San Diego/US
  • 17Clinical Research, Institut Gustave Roussy, Villejuif/FR
  • 18Medical Oncology, Hôpital Saint Louis, 75010 - Paris/FR
  • 19Biostatistics, Institut Gustave Roussy, 94800 - Villejuif/FR



CUP are heterogeneous tumors that share the unique characteristic of metastases with no identifiable origin. The outcome of patients (pts) with CUP is poor despite empiric chemotherapy that has activity against a wide variety of neoplasms such as the cisplatin-gemcitabine combination (Culine S, JCO 2002). Molecular tests may identify primary sites in up to 80% of pts, and results suggest that at least 1/3 of identified primaries may not be sensitive to empiric chemotherapy used in CUPs (Gross-Goupil G 2012). In the GEFCAPI 04 phase III trial, we hypothesized that tailored treatment will improve outcomes.


Eligible pts had pathologically-confirmed metastatic CUPs and were treatment naïve. Pts belonging to pre-defined favorable subsets were excluded. After relevant workup had identified no primary site, pts were randomized 1:1 to either Arm A (Cisplatin 100 mg/m² d1+ Gemcitabine 1250 mg/m², day 1 and 8, q3w) or Arm B (gene expression test followed by à la carte treatment according to the suspected primary). The test consisted of the Tissue Of Origin (Pathwork, n = 21) or CancerTYPE ID (Biotheranostics, n = 222). The primary endpoint was PFS (HR = 0.625, power=80%, 5% bilateral test). Stratification was on site, PS and LDH level. Secondary endpoints were PFS in pts with pre-defined cancers likely insensitive to cisplatin-gemcitabine and OS.


From 03/12 to 02/18, 243 pts from 4 EU countries were randomized (Arm A: 120, Arm B: 123). Primary cancers most often reported by tests were pancreatico-biliary cancer (19%), squamous cell carcinoma (11%, kidney cancer (8%), and lung cancer (8%). Treatment was tailored by molecular test results in 91/123 arm B pts (74%). PFS by central review was similar: HR = 0.95 (0.72-1.25); p = 0.7; medians: 5.3 m arm A vs 4.6 m arm B. PFS by local review also showed no significant difference: HR = 0.80 (0.60-1.06); p = 0.12; medians 5.8 vs 6.4 m. OS was also similar in the overall population (HR: 0.92 (0.69-1.23), medians: 10 vs 10.7 m) and in 60 pts with suspected cancers likely insensitive to GC.


In GEFCAPI 04, using a molecular test followed by tailored systemic treatment did not improve outcomes of pts with CUP.

Clinical trial identification


Editorial acknowledgement

Legal entity responsible for the study

Institut Gustave Roussy.


Programme Hospitalier de Recherche Clinique (PHRC) from the French Ministry of Health.


K. Fizazi: Advisory / Consultancy: Astellas; Advisory / Consultancy: AAA; Advisory / Consultancy: Bayer; Advisory / Consultancy: Clovis; Advisory / Consultancy: Curevac; Advisory / Consultancy: Incyte; Advisory / Consultancy: Janssen; Advisory / Consultancy: MSD; Advisory / Consultancy: Orion; Advisory / Consultancy: Sanofi. R. Morales Barrera: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: MSD; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Astrazeneca; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Asofarma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Johnson and Jonhson; Honoraria (self), Advisory / Consultancy: Roche. C.A. Schnabel: Full / Part-time employment: bioTheranostics. All other authors have declared no conflicts of interest.