BARCELONA, Spain – DNA profiling is revealing novel treatment choices for patients with cancer whose disease has spread by the time they are diagnosed and no primary tumour site of origin can be found – so-called carcinoma of unknown primary (CUP).
Research reported at the ESMO Congress 2019 showed that approximately one in three patients with CUP may not be adequately treated with standard chemotherapy but may be suitable for matched targeted treatment or immunotherapy based on DNA changes in their tumour. (1,2)
“Standard treatment for CUP has not changed in decades so, if we can change the outcome for the one in three patients with targetable mutations identified by DNA profiling, that could have an important impact on CUP therapy,” said Prof Jeffrey Ross, Upstate Medical University, Syracuse, USA, first author of one of the reported studies.
CUP affects approximately one in 15 patients with cancer, despite investigations to try to identify the primary tumour from which the cancer has spread. They then receive anti-cancer treatment and/or palliative care to relieve symptoms arising from the spread of their cancer. However, only about one in 10 patients survive for one year.
“CUP is a bit of a pariah because people don’t understand it and assume that nothing can be done. We need to change that attitude and encourage clinicians to look for and treat the drivers of each patient’s disease as shown by DNA profiling,” urged Ross.
An analysis of 303 CUP tissue samples collected in 2018, reported at the ESMO Congress 2019, used cutting edge technology to search for DNA changes and revealed that 32% could have been targeted by the latest medicines. (1) The same technology is now being used in the ongoing prospective CUPISCO trial. This is randomising patients with CUP to individualised targeted treatment or immunotherapy based on genetic alternations in their tumour, or to standard platinum-based chemotherapy. Initial results are expected within the next few years.
The need for a greater understanding of CUP tumour biology and a wider range of targeted therapies is reinforced by results of the GEFCAPI 04 trial, also reported at the ESMO Congress 2019. (2) Started in 2012, this study used gene expression technology to identify the most likely primary tumour source in patients with CUP. However, best available targeted and other treatment tailored to primary tumours failed to improve disease progression or survival compared to standard platinum–based chemotherapy.
“The GEFCAPI 04 results are disappointing but many of the patients had pancreatic, biliary and other kinds of cancer which are extremely difficult to treat and for which there are no targeted treatments. In a small number of patients who had suspected primary cancers unlikely to respond to empiric chemotherapy, molecular testing allowed use of a targeted agent or better tailored chemotherapy or immunotherapy. But there were probably not enough to make a difference to the overall results of the study,” said study first author Prof Karim Fizazi, Institute Gustave Roussy, University of Paris Sud, Villejuif, France.
“We need better tests, especially for the worst types of cancer, that not only tell us the identity of each patient’s primary tumour but also the detailed biology of their cancer and the potential targets for treatment. In addition, we need better weapons with which to attack those targets. It’s not enough to know what the targets are, we need to be able to do something about them,” concluded Fizazi.
Commenting on the results of the two presentations, Dr Harpreet Wasan, Hammersmith Hospital, Imperial College London, UK, underlined the importance of understanding the fundamental biology of CUP, and not just the origin of the primary tumour.
“Classifying CUP on the basis of a test that is pointing to its site of origin is not enough to improve patient outcomes. These are nasty tumours that behave much more aggressively and spread much earlier than a typical tumour that is diagnosed with a clear primary site. We therefore need a better understanding of the biology that is driving CUP in the sites where it is found rather than where it started, so we can choose the most relevant targeted therapy,” said Wasan.
“We now know that a third of patients with CUP could get tailored treatment that is already available. We don’t yet know if this approach improves their outcomes and that is what the very important CUPISCO trial is designed to show. For clinicians today, there is still significant value in rapidly testing for the site of origin with modern approaches in patients with suspected CUP in case there is a primary tumour that has been missed, especially in general hospitals where more complex testing is not available. This has been demonstrated as being practical in the GEFCAPI 04 trial, despite the disappointing survival results. The diagnosis is very important from a patient’s perspective as those with CUP are amongst the most vulnerable we see. However, for the future, as DNA profiling becomes more widely available and the range of targeted therapies increases, we can hopefully expect a more positive outlook for patients with CUP,” he added.
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References
- Abstract 1983PD_PR ‘Comprehensive genomic profiling (CGP) of carcinoma of unknown primary origin (CUP): retrospective molecular classification of potentially eligible patients (PTS) for targeted or immunotherapy treatment (TX) using the prospective CUPISCO trial’s criteria’ will be presented by Jeff Ross during the Poster Discussion Session on Sunday, 29 September, 16:30-17:45 CEST in Alicante Auditorium (Hall 3). Annals of Oncology, Volume 30, Supplement 5, October 2019
- Abstract LBA15_PR ‘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)’ will be presented by Karim Fizazi during the Proffered Paper Session on Saturday, 28 September, 08:30-10:00 CEST in Pamplona Auditorium (Hall 2). Annals of Oncology, Volume 30, Supplement 5, October 2019
J.S. Ross1, E.S. Sokol2, H. Moch3, L. Mileshkin4, G. Baciarello5, F. Losa6, A. Beringer7, M. Thomas7, S. Foser7, J. Elvin8, N. Danziger8, N. Ngo8, J.Y. Tse8, K. Killian8, D.X. Jin9, L.M. Gay8, A. Krämer10
1Pathology And Urology, Upstate Medical University, Syracuse, United States of America, 2Cancer Genomics, Foundation Medicine, Cambridge, United States of America, 3Department Of Pathology And Molecular Pathology, University Hospital Zurich, Zurich, Switzerland, 4Department Of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia, 5Department Of Medical Oncology, Institut Gustave Roussy, Villejuif, France, 6Medical Oncology Department, Hospital de Sant Joan Despí Moisès Broggi, Barcelona, Spain, 7Personalised Healthcare Oncology, Global Product Development Medical Affairs, F. Hoffmann-La Roche Ltd, Basel, Switzerland, 8Pathology Group, Foundation Medicine, Inc., Cambridge, United States of America, 9Product Development, Foundation Medicine, Inc., Cambridge, United States of America, 10Clinical Cooperation Unit Molecular Hematology/oncology And Department Of Internal Medicine V, German Cancer Research Center (DKFZ) and University of Heidelberg, Heidelberg, Germany
Background: Standard CUP therapy has not changed for decades. CUPISCO (NCT03498521) is an ongoing randomised prospective trial using CGP to assign CUP pts to individualised targeted or immunotherapy arms (molecularly guided therapy; MGT).
Methods: Archival tissue from 303 centrally reviewed undifferentiated- and adeno-CUP cases in the FoundationCore™ database underwent hybrid capture-based CGP (FoundationOne® CDx). Microsatellite instability (MSI), tumour mutational burden (TMB) and genomic loss of heterozygosity (gLOH) were calculated (Frampton Nat Biotechnol 2013; Swisher Lancet Oncol; Chambers Genome Med 2017). PD-L1 expression was measured by DAKO 22C3 immunohistochemistry. Pts were classified by whether CGP results could have informed assignment to CUPISCO arms; TTF-1+, CK7–/CK20+/CDX2+ or TMPRSS2:ERG+ cases were excluded.
Results: The sex ratio was 1:1; median age was 67 yrs (range 22–89+). CGP revealed 96 pts (32%) matched to a CUPISCO arm (Table).
CUPISCO arm |
% Genomic alterations |
|---|---|
Alectinib |
0.66 |
Vismodegib |
1.32 |
Ipatasertib |
8.25 |
Olaparib |
5.61 |
Erlotinib + bevacizumab |
2.31 |
Vemurafenib + cobimetinib |
2.97 |
Subcutaneous trastuzumab + pertuzumab + chemo |
9.24 |
Atezolizumab |
9.24 |
Entrectinib (in development) |
0.33 |
Mean TMB was 8 mut/Mb; 23% had ≥10 (low), 12%, ≥16 (int) and 9%, ≥20 (high). 3 (1%) had high MSI and 20%, gLOH ≥16. 42 (14%) had high PD-L1 (tumour proportion score ≥50%). Key genomic alterations included HER2 (7%), PIK3CA, NF1 (6% each), NF2 (5%), BRAF, PTEN, FGFR2, EGFR, MET (all 4%), CDK6 (3%), FBXW7 and CDK4 (2% each). Key gene fusions involved ALK, RET and ROS1 (all 1%). KRAS was mutated in 27%; 6% had G12C alterations. Of the 23 assessable high TMB cases, 8 (35%) had a tobacco and 5 (22%) a UV light or mismatch repair mutational signature. 20% of cases harboured a putative cancer-associated germline DNA mutation.
Conclusions: 32% of CUP pts would have been potentially eligible for MGT in CUPISCO. Future studies including additional biomarkers, such as PD-L1–positivity and gLOH, may identify a greater proportion of CUP pts potentially benefitting from individualised treatment.
Editorial acknowledgement: Support for third-party editing assistance for this abstract, furnished by Daniel Clyde, PhD, of Health Interactions, was provided by F. Hoffmann-La Roche Ltd, Basel, Switzerland.
Legal entity responsible for the study: F. Hoffmann-La Roche Ltd
Funding: F. Hoffmann-La Roche Ltd
Disclosure: J.S. Ross: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine, Inc.; Non-remunerated activity/ies, Support for third-party editing assistance: F. Hoffmann-La Roche Ltd.
E.S. Sokol: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine, Inc; Non-remunerated activity/ies, Support for third-party editing assistance: F. Hoffmann-La Roche Ltd.
H. Moch: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: F. Hoffmann-La Roche Ltd ; Advisory / Consultancy, Travel / Accommodation / Expenses: Definiens AG; Non-remunerated activity/ies, Support for third-party editing assistance: F. Hoffmann-La Roche Ltd .
L. Mileshkin: Travel / Accommodation / Expenses: F. Hoffmann-La Roche Ltd; Travel / Accommodation / Expenses: Beigene; Non-remunerated activity/ies, Support for third-party editing assistance: F. Hoffmann-La Roche Ltd.
G. Baciarello: Honoraria (self), Travel / Accommodation / Expenses: F. Hoffmann-La Roche Ltd; Honoraria (self), Travel / Accommodation / Expenses: Astellas; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Janssen; Honoraria (self), Travel / Accommodation / Expenses: Ipsen; Honoraria (self): Amgen; Travel / Accommodation / Expenses: AstraZeneca; Non-remunerated activity/ies, Support for third-party editing assistance: F. Hoffmann-La Roche Ltd; Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi.
F. Losa: Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (institution), Travel / Accommodation / Expenses: F. Hoffmann-La Roche Ltd; Advisory / Consultancy, Speaker Bureau / Expert testimony: Sanofi; Advisory / Consultancy, Research grant / Funding (institution): Amgen; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Merck; Advisory / Consultancy: Servier; Non-remunerated activity/ies, Support for third-party editing assistance: F. Hoffmann-La Roche Ltd.
A. Beringer: Full / Part-time employment, Non-remunerated activity/ies, Support for third-party editing assistance: F. Hoffmann-La Roche Ltd.
M. Thomas: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Non-remunerated activity/ies, Support for third-party editing assistance: F. Hoffmann-La Roche Ltd.
S. Foser: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment, Non-remunerated activity/ies, Support for third-party editing assistance: F. Hoffmann-La Roche Ltd.
J. Elvin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine, Inc; Non-remunerated activity/ies, Support for third-party editing assistance: F. Hoffmann-La Roche Ltd.
N. Danziger: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine, Inc; Non-remunerated activity/ies, Support for third-party editing assistance: F. Hoffmann-La Roche Ltd.
N. Ngo: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine, Inc; Non-remunerated activity/ies, Support for third-party editing assistance: F. Hoffmann-La Roche Ltd.
J.Y. Tse: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine, Inc; Non-remunerated activity/ies, Support for third-party editing assistance: F. Hoffmann-La Roche Ltd.
K. Killian: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine, Inc; Full / Part-time employment, Special Volunteer: National Cancer Institute; Shareholder / Stockholder / Stock options, Non-remunerated activity/ies, Support for third-party editing assistance: F. Hoffmann-La Roche Ltd.
D.X. Jin: Shareholder / Stockholder / Stock options, Full / Part-time employment: Foundation Medicine, Inc; Shareholder / Stockholder / Stock options, Non-remunerated activity/ies, Support for third-party editing assistance: F. Hoffmann-La Roche Ltd.
L.M. Gay: Full / Part-time employment, Current: Ellem Consulting; Non-remunerated activity/ies, Support for third-party editing assistance: F. Hoffmann-La Roche Ltd; Full / Part-time employment, Previous: Foundation Medicine, Inc.
A. Krämer: Honoraria (self), Honoraria (institution), Advisory / Consultancy, Travel / Accommodation / Expenses, Non-remunerated activity/ies, Support for third-party editing assistance: F. Hoffmann-La Roche Ltd; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Daiichi Sankyo; Honoraria (self), Advisory / Consultancy: Abbvie; Honoraria (institution), Research grant / Funding (institution): Bayer; Advisory / Consultancy: BMS; Travel / Accommodation / Expenses: Celgene; Research grant / Funding (institution): Merck.
K. Fizazi1, A. Maillard2, N. Penel3, G. Baciarello4, D. Allouache5, G. Daugaard6, A. Van de Wouw7, G. Soler8, E. Vauleon9, L. Chaigneau10, R. Jansen11, F. Losa Gaspa12, R. Morales Barrera13, C. Balana14, D. Tosi15, B. Chauffert16, C.A. Schnabel17, G. Martineau18, S. Culine19, I. Borget20
1Oncology, Gustave Roussy, University of Paris Sud, Villejuif, France, 2Biostatistics, Gustave Roussy, Villejuif, France, 3General Oncology Department, Centre Oscar Lambret, Lille, France, 4Cancer Medicine, Gustave Roussy, Villejuif, France, 5Medical Oncology, Centre Francois Baclesse, Caen, France, 6Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark, 7Medical Oncology, Medisch Centrum voor Noord-Limburg, Venlo, Netherlands, 8Medical Oncology, Institut Català d´Oncologia, Barcelona, Spain, 9Medical Oncology, Centre Eugene - Marquis, Rennes, France, 10Medical Oncology, CHRU Jean Minjoz, Besançon, France, 11Medical Oncology, Maastricht University Medical Center, Maastricht, Netherlands, 12Medical Oncology, Hospital Moises Broggi, Barcelona, Spain, 13Medical Oncology Dept., Vall d'Hebron University Hospital, Barcelona, Spain, 14Medical Oncology, Germans Trias i Pujol, Barcelona, Spain, 15Department Of Medical Oncology, ICM Regional Cancer Institute of Montpellier, Montpellier, France, 16Medical Oncology, CHU Amiens, Amiens-Picardie, France, 17Biology, bioTheranostics, Inc., San Diego, United States of America, 18Clinical Research, Institut Gustave Roussy, Villejuif, France, 19Medical Oncology, Hôpital Saint Louis, Paris, France, 20Biostatistics, Institut Gustave Roussy, Villejuif, France
Background: 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 3 trial, we hypothesized that tailored treatment will improve outcomes.
Methods: 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.
Results: 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.
Conclusions: In GEFCAPI 04, using a molecular test followed by tailored systemic treatment did not improve outcomes of pts with CUP.
Clinical trial identification: 2011-A01202-39
Legal entity responsible for the study: Institut Gustave Roussy
Funding: Programme Hospitalier de Recherche Clinique (PHRC) from the French ministry of health
Disclosure: 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.
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