(P 135) PREDICTIVE VALUE OF ISG15 AND PPAP2B IN SOLITARY FIBROUS TUMOR TREATED WITH SUNITINIB AND NIVOLUMAB: A CORRELATIVE STUDY FROM IMMUNOSARC, A SPANISH GROUP FOR RESEARCH ON SARCOMA (GEIS) PHASE II TRIAL

Objective: There is cumulative evidence that solitary fibrous tumor (SFT) is sensitive to antiangiogenics. In a previous clinical trial, ISG15 expression showed predictive/prognostic value in SFT patients treated with pazopanib. This cohort of the Phase II IMMUNOSARC study, tested the activity of sunitinib (SUN) plus nivolumab (NI) in SFT patients. Gene expression signatures have revealed additional potential biomarkers for these combination. Correlative studies aimed to explore these predictive biomarkers in the SFT cohort.

Methods: Adult patients with centrally confirmed SFT, advanced and progressing disease, received SUN 37.5mg (2 weeks of induction) and then 25mg per day concomitant with NI 240mg iv every 2 weeks. A mandatory biopsy was collected at baseline in all patients. Primary end-point was progression-free survival rate at 6 months (6m-PFR) by Choi. Minimax Simon’s two-stage [H0 35% and H1 65% (α 0.05 and β 0.1)], defined a first stage in which at least 6 patients should have 6m-PFS from 14 evaluable patients. If this occurred, 10 additional patients would be enrolled. Direct-transcriptomics analysis, with the Oncology Biomarker Panel of HTG Molecular (EdgeSeq technology) were performed in baseline biopsies. PFS gene signatures were derived using unsupervised clustering. MAXSTAT method was used to categorize gene expression according to PFS, and direct transcriptomic counts of selected genes (ISG15 and PPAP2B) were jointly discretized into two (low, high) levels each using Hartemink’s method

Results: From October 2019 to November 2020, 16 patients (9 male/ 7 female, median age 47 years (33-59), 13 patients previously treated) were enrolled. 13/16 patients were metastatic at study entry. With a median follow-up in alive patients of 16 months (2-27), 6m-PFR was 5/16 (31.3%), with a median PFS of 4.14 months (95%CI 1.7-6.6). Non pretreated patients had a longer PFS than those pretreated patients (5.5 months (95%IC 1-13) vs 3.5 months (95%IC 2.2-4.9), p=0.02). Median overall survival was 16.1 months (95%CI 5.5-26.7) for the whole series. ISG15 and PPAP2B were found as differentially expressed between different PFS groups. The obtained cutoffs for MAXSTAT according to PFS were ISG15: 2298 and PPAP2B: 3522 counts. Patients with ISG15 levels above the cut-off presented a worse PFS (1.5months 95%CI 0.8-2.1) when compared with those with ISG15 levels below the cut-off (5.4 months 95%CI 4.8-6.1), p=0.001. Patients with PPAP2B levels above the cut-off presented a better PFS (6.6 months 95%CI 3.4-9.9) when compared with those with PPAP2B levels below the cut-off (2.79 months 95%CI 0.9-4.6), p=0.001. When combined, patients with lower levels of ISG15 and higher levels of PPAP2B had a better PFS (6.6months, 95%CI 0-14.2) vs those with higher levels of ISG15 and lower levels of PPAP2B (median PFS 1.5 months (95%CI 1.3-1.7), p< 0.0001.

Conclusion: The study did not achieve the prespecified conditions of the first stage of Simon and recruitment has been closed in this cohort. A combined score with PPAP2B and ISG15 expression was able to describe with different PFS groups, constituting a potential predictive score to the combination of sunitinib and nivolumab.