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Treatment Tailored by Molecular Gene Expression Analysis Fails to Improve Outcome in Patients with CUP

Systemic treatment based on molecular analysis did not improve survival over empiric chemotherapy in patients with carcinomas of unknown primary site
28 Sep 2019
Translational Research
Carcinoma of Unknown Primary Site (CUP)

Treatment tailored to the suspected primary site of origin, as identified by comprehensive molecular gene expression analysis of tumours from patients with carcinomas of unknown primary (CUP)site, did not improve progression-free survival (PFS) over empiric chemotherapy consisting of cisplatin plus gemcitabine, investigators reported at the ESMO Congress 2019 in Barcelona, Spain.

CUP are heterogeneous tumours that are uniquely characterised by metastases having no identifiable origin. Patients with CUP generally have poor outcomes, even though empiric chemotherapy, such as cisplatin plus gemcitabine, with broad activity against a wide variety of neoplasms is available and has demonstrated efficacy,1 according to Karim Fizazi, Gustave Roussy, University of Paris Sud, in Villejuif, France. He explained further that molecular tests identify primary sites in up to 80% of patients and results suggest that at least one-third of identified primaries may not be sensitive to empiric chemotherapy used in CUPs.2

Professor Fizazi and a team of internationally-based investigators reasoned that treatment tailored to the suspected primary site of origin could improve patient outcome. The investigators conducted the phase III GEFCAPI 04 trial (2011-A01202-39), which enrolled treatment naive patients with pathologically-confirmed metastatic CUPs. Patients in pre-defined subsets with a more favourable prognosis were excluded from enrolment.

Patients undergoing a relevant work-up that identified no primary site were randomised 1:1 to arm A for treatment with cisplatin at 100 mg/m² on day 1 plus gemcitabine at 1250 mg/m² on days 1 and 8, every 3 weeks (n=120) or to arm B, where they were given a gene expression test followed by treatment tailored to the suspected primary site (n=123). Twenty-one patients received the Tissue Of Origin (Pathwork) test and 222 received the CancerTYPE ID (Biotheranostics) test.

The primary endpoint of the study was PFS (hazard ratio [HR] 0.625, 80% power, 5% bilateral test). Stratification was according to site, performance status and baseline LDH level. Secondary endpoints included PFS in patients with pre-defined cancers that were likely to be insensitive to cisplatin-gemcitabine, and overall survival (OS).

Primary and secondary endpoints were not met

Molecular testing most often identified pancreatico-biliary cancer (19%), squamous cell carcinoma (11%), kidney cancer (8%), and lung cancer (8%) as the primary cancer.

Treatment tailored by the molecular test results was administered to 91 patients (74%) in arm B. However, PFS by central review in these patients was similar to that demonstrated by patients in arm A receiving gemcitabine and cisplatin; median PFS was 5.3 months compared to 4.6 months, respectively (HR 0.95; 95% confidence interval [CI], 0.72-1.25; p = 0.7).

No significant difference in PFS was observed between the treatment groups according to local review. Median PFS by local review was 5.8 months in arm B compared to 6.4 months in arm A (HR 0.80; 95% CI, 0.60-1.06; p = 0.12).

The comparison of OS in the overall population with a cohort of 60 patients with suspected cancers likely to be insensitive to gemcitabine/cisplatin (secondary endpoint) showed similar results, where median OS was 10.0 months versus 10.7 months, (HR 0.92; 95% CI, 0.69-1.23).


Professor Fizazi and the co-authors concluded thatusing a molecular analysis to identify the primary site of origin followed by tailored systemic treatment did not improve outcomes of patients with CUP in the GEFCAPI 04 study.


This study was funded by Programme Hospitalier de Recherche Clinique (PHRC) from the French Ministry of Health.


  1. Culine S, Kramar A, Saghatchian M, et al. Development and validation of a prognostic model to predict the length of survival in patients with carcinomas of an unknown primary site. J Clin Oncol2002; 20(24):4679-83.
  2. Gross-Goupil G, Fourcade A, Blot E, et al. Cisplatin alone or combined with gemcitabine in carcinomas of unknown primary: Results of the randomised GEFCAPI 02 trial. Eur J Cancer 2012; 48(5):721-7.


LBA15_PR – Fizazi K,Maillard A, Penel N, et al. A phase 3 trial of empiric chemotherapy with cisplatin and gemcitabine or systemic treatment tailored by molecular gene expression analysis in patients with carcinomas of an unknown primary (CUP) site (GEFCAPI 04).

Last update: 28 Sep 2019

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