Circulating biomarkers and outcomes in a single arm phase 2 trial of first line sunitinib alternating with everolimus for advanced renal cell carcinoma ANZUP 0901—The EVERSUN trial 1,2
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Sonia Yip , Nick Pavlakis , Rozelle Harvie , Andrew Martin , Lidija Jovanovic , Amanda Hudson , Jennifer F. Thompson , Colleen Nelson , Anne Long , Christopher Steer , Michelle L. Harrison , George Kannourakis , David Goldstein , Ganessan Kichenadasse , Raymond M. Lowenthal , Martin R. Stockler , Ian D. Davis , Australian & New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group. 1
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Sydney Catalyst Translational Cancer Research Centre, Sydney, Australia, NHMRC Clinical Trials Centre, University of Sydney, Sydney, Australia, Royal North Shore Hospital, Sydney, Australia, Bill Walsh Cancer Research Laboratories, Kolling Institute, Sydney, Australia, Australian Prostate Cancer Research Centre-Queensland, Queensland University of Technology, Brisbane, Australia, Border Medical Oncology, Wodonga, Australia, 7 8 9 11 12 10 Royal Prince Alfred Hospital, Sydney, Australia, Ballarat Oncology & Haematology Services, Ballarat, Australia, Prince of Wales Hospital, Sydney, Australia, Flinders Medical Centre, Flinders University, Adelaide, Australia, Royal Hobart Hospital, Hobart, Australia, Monash University Eastern Health Clinical School, Box Hill, Australia
AIM
METHODS
RESULTS
DISCUSSION
To determine associations between levels of circulating biomarker at baseline and clinical outcomes in advanced renal cell carcinoma (aRCC) being treated with an alternating regimen of sunitiinib and everolimus.
Participants from a single-arm, two-stage, multicentre, phase 2 trial of first line alternating regimen of sunitinib and everolimus (EVERSUN trial).
Participant characteristics (n=55) Mean age 61 years Male 71%, female 29% MSKCC favourable risk 16%, intermediate risk 84% 47 progression events and 30 deaths after a median follow-up of 20 mo Circulating tumour cells Detected in 5/31 (16%) tested. Median no. of CTCs enumerated in positive patients 1 / 7.5mLs (range 1 to 6). Serum biomarkers
Circulating tumour cells We found circulating tumour cells (CD45-, EpCAM+, cytokeratins 8, 18+, and/ or 19+) in 16% of our patients with clear cell RCC. This lies within the range reported in the literature of EpCAM+ve clear cell 1 RCC tumours: primary (20%) and metastases (14%) . Others have found higher rates of circulating tumour cells of 32-53% and may be attributed to (i) a different method to detect these cells (CD45 autoMACS depletion followed by cytokeratin immunohistochemistry) and (ii) 2-4 other researchers did not distinguish patients by RCC subtype .
INTRODUCTION The trial was a first line alternating regimen of targeted therapies of sunitinib (tyrosine kinase inhibitor) and everolimus (mTOR inhibitor) - the EVERSUN trial (Abstract # 438). The translational study (EVERSUN-T) analysed biomarkers including: circulating tumour cells and proteins relevant to pathways targeted by sunitinib and everolimus.
Trial treatment administered in 12-week cycles; 4 weeks of sunitinib (50 mg once daily) followed by 2 weeks rest, then 5 weeks of everolimus (10 mg once daily) followed by 1 week rest Participants moved to single-agent treatment after first progression and continued on single-agent until further progression. Clinical outcomes: progression free survival (PFS), overall survival (OS), objective tumour response (OTR) *where OTR = complete response (CR) + partial responses (PR)+, and toxicity (cycle 1 grade 3-5 AEs). Circulating tumour cells: Baseline whole blood collected for enumeration of circulating tumor cells (CTCs) of epithelial origin (CD45-, EpCAM+, and cytokeratins 8, 18+, and/or 19+) using the CellSearch® CTC system (Veridex). Serum biomarkers: Serum recovered for testing of 15 protein biomarkers by multiplex immunoassays (Bio-Plex® system, BioRad) or ELISA (R&D Systems). Group Cell stress-related
Associated with
Test statistic (p value)
Higher OTR
low levels of bFGF
6 vs 0 PRs (p 0.009)
Shorter OS
high levels of NGAL
HR 2.5 (p 0.02)
IL-8
HR 2.3 (p 0.04)
detectable levels of CAIX
OR 4.7 (p 0.03)
NGAL
PFS was not associated with any analysed biomarkers on univariable analysis
bFGF (FGF2)
PDGF
PLGF
VEGF-A,-C,-D
sVEGFR-2,-3 CAIX
Pro-inflammatory cytokine
IL-8
Transcription factors related to hypoxia
HIF-1,-2
Other markers of response to sunitinib
E-selectin
Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography © 2013. All Rights Reserved
Clinical Endpoint
Toxicity
HIF-regulated transmembrane protein
Figure 1 Multiple targets in the treatment of RCC. Rini BI et al J Clin Oncol 2009 27: 3225-34.
Univariable analyses
Biomarker
Growth factors Growth factor receptors
Associations between Serum Biomarkers at Baseline and Clinical Endpoints
Multivariable analyses adjusting for MSKCC prognostic score, age, gender and presence of liver or bone metastases) Clinical Endpoint
Associated with
Test statistic (p value)
Shorter PFS
high bFGF
HR 2.0 (p 0.03)
low VCAM-1
HR 0.50 (p 0.04)
undetectable HIF1
HR 0.33 (p 0.01)
high NGAL
HR 2.5 (p 0.03)
undetectable HIF1
HR 0.35 (p 0.04)
detectable CAIX
OR 5.8 (p 0.04)
Shorter OS VCAM-1
Toxicity
Taking into account the number of analyses performed, no associations were statistically significant after adjusting for multiple comparisons.
Serum biomarkers - baseline Taking into account the number of analyses done, none of these associations were statistically significant when adjusted for multiple comparisons. However, we found that low bFGF was associated with longer PFS and higher objective response rate detectable CAIX was associated with worse toxicity are interesting. These findings were unexpected and warrant further assessment in other datasets.
CONCLUSIONS 1. Circulating tumour cells were detected in only 16% of these patients with untreated, clear cell advanced RCC. 2. We did not find strong statistical evidence for the prognostic value of these circulating biomarkers at baseline. 3. Other data sets should be assessed for associations between: low bFGF, response and PFS; and detectable CAIX levels and toxicity. 4. We are currently assessing the prognostic value of changes from baseline in these biomarkers.
References 1. Went et al 2005 Am J Surg Pathol 29:83-8 2. Bilkenroth et al 2001 Int J Ca 92:577-82 For all enquiries:
[email protected] Abstract ID # 428
Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12609000643279
3.Bleumke, et al 2009 Ca Epid Biomarker Prev 18:2190-4
This study was conducted by the Australian and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group Ltd in collaboration with the NHMRC Clinical Trials Centre at the University of Sydney. ANZUP acknowledges the financial support received from Cancer Australia and the Cancer Institute NSW. Novartis provided study drug (everolimus) and financial support for this trial.
4. Meye et al 2002 Int J Oncol 20:521-30
