1. RESULTS BACKGROUND METHODS RESULTS CONCLUSIONS CONTACT
 Translational study associated to a phase II study evaluating the activity of pazopanib in patients (pts) with advanced/metastaticliposarcoma (LPS): A joint Spanish Sarcoma Group (GEIS) and German Interdisciplinary Sarcoma Group (GISG) study
Claudia Valverde 1, Antonio Fernández-Serra2, Marta Ramírez-Calvo2, Jose A. Lopez-Martin3, Cleofé Romagosa1, Juan Antonio Carrasco4, Sebastian Bauer5, Javier Martínez Trufero6, Fina Cruz7, Peter Reichardt8, Cesar Serrano1, Viktor Grünwald9, Rafael Morales1, Oscar Persiva 1, Diego Varona1, Bernd Kasper10, Pablo Luna11, Javier Martin12, Amparo Ruíz-Sauri13, José Antonio López-Guerrero2 1 Vall d´ Hebrón University Hospital, Barcelona, Spain, 2 Fundación Instituto Valenciano de Oncología, Valencia, Spain, 3 12 de Octubre University Hospital & Research Institute, Madrid, Spain, 4 Complejo Universitario de Vigo, Vigo, Spain, 5 Universitätsklinikum Essen, Essen, Germany, 6 Hospital Miguel Servet, Zaragoza, Spain, 7 Hospital Universitario Canarias, Tenerife; Spain, 8 HELIOS Klinikum Berlin-Buch, Germany, 9 Medical School Hannover, Hannover, Germany 0 Mannheim University Medical Center, Mannheim, Germany 11 Hospital Son Espases, Mallorca, Spain 12 Hospital Virgen del Rocío, Sevilla; Spain 13 University of Valencia, Spain
Abstract nº 11067
ASCO 2019
BACKGROUND
Table 1. Baseline characteristics
RESULTS
TOTAL
POPULATION
TRANSLATIONAL
LONG
RESPONDERS
 GEIS 30
Cohort A
Cohort B N 37 15 28 11 13 3
Median age (years)
61 (38-88)
49 (25-73) 61 48 49
Sex (Male)
59.5%
40%
56%
44%
54%
66%
ECOG 0 vs 1
59.5% vs 40.5%
57.1% vs 42.9%
56 vs 36%
40 vs 60%
60 vs 40%
50 vs 50%
Primary tumor
Extremities
2 (5.8%)
13 (92.8%) 4%
90% 0%
Retroperitoneum
27 (65.7%)
1 (7%)
68%
88%
Time from first treatment to study entry ( years)
4.4 ( )
5.6 ( )
2.6
2.4
2.5
Best response to previous chemo
CR+PR
14.8%
58.3%
18%
10% SD
44.4%
25.1%
37%
30%
42.8%
100%
Number of previous lines
2 (1-4)
2(1-4)
2.5 (1-4)
1.5 (1-4)
Liposarcomas (LPS) are soft tissue sarcoma (STS) which account for at least 20% of all STS in adults. They can be further classified into histologically and biologically different subtypes: well-differentiated LPS/de-differentiated LPS (40%), myxoid or round cell LPS (about 45%) and pleomorphic LPS (5-10%).
Few therapeutic options are currently available for patients (pts) with unresectable, locally advanced, or metastatic STS including anthracyclines, ifosfamide, trabectedine, gemcitabine, dacarbazine, docetaxel and more recently eribuline. Following the positive results of the phase III study PALETTE, Pazopanib, a multikinase inhibitor, has been added to the arsenal as second or later line treatment for advanced non-adipocytic soft-tissue sarcoma.
GEIS 30 was a phase II non-randomized study with the main objective of assessing progression-free survival (PFS) at 12 weeks (w) in two different cohorts of LPS (cohort A well-differentiates/dedifferentiated LPS and B: myxoid/rpound cell LPS). The main inclusion/exclusion criteria were:Pts ≥18 years old, ECOG 0-1, with high- or intermediate-grade LPS (excluding pleomorphic) with locally advanced or metastatic measurable disease (per RECIST 1.1) . Pts had to be unsuitable or should have failed at least to one line of systemic therapy but no more than 3 lines. Central pathologic review was performed before study entry to confirm diagnosis and assign the patient into one of the two cohorts. All patients received pazopanib 800 mg once daily until tumor progression, unacceptable toxicity, death, or pt’s withdrawal.
The study showed moderate activity of pazopanib in well-differentiated/dedifferentiated LPS (cohort A:37 pts, PFS at 12 weeks (w) 43.2%) and no activity in Myxoid/round cell LPS (cohort B: 15 pts, PFS at 12w 13.3%). In fact, cohort B was closed after the first Simon stage due to insufficient activity. The toxicity profile was similar to other previously reported studies.
The present associated translational study aims to identify tumor and plasma biomarkers that are differently expressed in long responders ( LRs) defined as PFS >24 weeks A B C
G_CSF
METHODS
AGO
BMP9
pg/ml
 Samples: Serum samples and paraffin-blocks at diagnosis were collected for 28 pts in cohort A and 11 in B (for the 13 remaining patients, the material had been exhausted during pathological revision or was of insufficient quality for analysis). A total of 16 pts were LRs (13 cohort A and 3 cohort B). Serum samples were obtained at baseline (t=0), after 3 w of treatment (t=2) and at progression (t=3).
A panel of 15 cytokines and growth factors were evaluated using Luminex technology (Millipore).
Paraffin-blocks were evaluated for microvessel density (MVD) by CD31 immunostaining and Image Pro-Plus 7.0 Image Analysis System (Media-Cybernetics).
For RNA expression analysis, the Oncology Biomarker Panel with probes for 2559 transcripts was used (HTG Molecular Diagnostics). 
pg/ml
pg/ml
Figure 2: Gene expresión stratifies patients in arm A in prognostic groups A) Heatmap of the separation in 2 clusters B) Heatmap with 3 clusters C) Kaplan-Meier curves representing the prognostic value of the 2 groups clustering with the Overall Survival (p=0,00062 D) Kaplan-Meier curves of the 3 groups clustering according Overall Survival (p=0,0015). D
AGO (BASAL) E
G_CSF (BASAL) F
MDV 1 1
RESULTS
0.75
0.75
CONCLUSIONS
Basal characteristics of the total popularion of GEIS 30 and of the 28 pts included in the translational study are sumarised in table 1.
Serum cytokines showed that expression of angiopoietin (AGO) and BMP9 decreases during treatment, whereas GCSF increases. In addition, G_CSF overexpression at baseline was associated with worse prognosis in arm B (p = 0.01) and AGO overexpression had a tendency in arm A (p = 0.09) respectively. (fig 1, A-E)
MVD: No differences between study arms and outcome were appreciated by MVD. (fig , F1)
RNA expression analysis. Gene expression revealed differences in some immunomodulators: PD-L1 was correlated with serum cytokines VEGFD (p = 0.04) and LEPTIN (p = 0.02); and PD-1 with VEGFD (p = 0.04), LEPTIN (p = 0.02), VEGFA (p = 0.02) and ANGIO (p = 0.03). PD-1, in addition,was overexpressed in LRs (p = 0.05).
Interestingly, three groups were identified in cohort A according to gene expression: Cluster 1, characterized by short-responder patients with the shortest overall survival, whereas cluster 3 (40% LRs) and 2 (63.6% LRs) showed longer survival rates (Overall Survival) (14.3%, 45.5% and 30% respectively) (p = 0.001) (fig. 2).
The clusters are separated according to the expression of 151 genes included in the analysis, among these could be outlined: CHI3L1, CXCL9, THBS4, SOD2, CYP1B1 and SERPINE1.
SURVIVAL PROBABILITY
SURVIVAL PROBABILITY
0.5
0.5
Gene expression profiling unveils three WD/DD-LPS biotypes according to their response to pazopanib, which, if confirmed, could be potentially used to select pts for treatment
Cohort B
0.25
0.25
Cohort A P=
P= 0.01
CONTACT
Principal investigator: Dra. Claudia M Valverde Address for correspondence: Hospital Universitario Vall d'Hebron, Passeig Vall d'Hebron , Barcelona EudraCT number: ClinicalTrials.gov Identifier: NCT
Figure 1: Differential expression of citoquines during treatment ( 0= baseline, 2= after 3w, 3= at progression) A) Angiopoietin expression tend to decrease during treatment B) BMP9 shows the same behavior C) G_CSF increases its expression D) Angiopoietin overexpression at baselinehad a trend towards worse prognosis in arm A E) G_CSF overexpression at baseline was associated with worse prognosis in arm B F) Microvascular Density Vessel was not different between groups.
Trial sponsorized by Novartis.