(P 170) HETEROGENEITY OF PAZOPANIB ACTIVITY ACROSS SOFT TISSUE SARCOMA SUBTYPES - A RETROSPECTIVE ANALYSIS OF 303 CASES FROM A REFERENCE CENTER

Objective: Pazopanib was authorized for the treatment of soft tissue sarcoma (STS) over 10 years ago, and since then, any novel tyrosine kinase inhibitor has been approved in this indication. Median progression-free survival (PFS) achieved in the phase III PALETTE trial was modest (4.6 months), but pazopanib showed a nearly 70% reduction in risk of disease progression compared to the placebo. In the current study, we aimed to analyze real-world evidence of the activity of pazopanib in patients with advanced STS treated in a reference center.

Methods: We retrospectively analyzed the medical data of patients who commenced treatment with pazopanib between November 2012 and December 2021. Demographic and clinicopathological data were extracted. PFS, overall survival (OS), and duration of response (DoR) were estimated with the Kaplan-Meier method, and a comparison between groups was performed with a long-rank test. Cox regression was used for multivariate analysis. The growth Modulation index (GMI) was calculated as PFS on pazopanib divided by PFS on therapy given immediately before pazopanib. Metastases-free interval (MFI) was defined as the time from curative treatment to the development of metastatic or unresectable disease.

Results: A total number of 303 patients has been identified. The median age was 53 years (range 18-88), 50.2% (n=152) were female, 82.2% (n=249) underwent curative surgery for the primary tumor, and 24.8% (n=75) had distant metastases at diagnosis. The most common sarcoma subtypes were leiomyosarcoma (LMS; 28.4%; n=86), synovial sarcoma (SS; 18.2%, n=55), and undifferentiated pleomorphic sarcoma (UPS; 15.8%, n=48). The majority of patients received treatment at the metastatic stage (92.7%; n=281) in 3rd or 4th line of therapy, in 32.0% (n=97) and 31.7% (n=96), respectively. Lung (73.9%, n=224) was the most common location of metastases. 39.3% (n=119) of patients required a temporary hold of pazopanib, and 24.8% (n=75) required dose reduction.
Median PFS was 3.7 months (95%CI 2.9-4.4). 44.2% (n=134) of patients had GMI>1.3, indicating a better activity than previous line therapy. There were significant differences in PFS depending on histological subtype, with the longest median PFS in solitary fibrous tumor (SFT) (11.1; 95%CI 9.2-12.9), desmoplastic small round cell tumor (DSRCT) (7.4; 95%CI 2.1-12.7) and SS (5.5; 95%CI 3.1-7.8). PFS was significantly longer in women (4.6 vs. 2.8; p< 0.001) and in patients with MFI>10 months (4.2 vs. 3.0; p=0.012). Multivariate analyses confirmed female gender, SFT and SS, and MFI>10 to be associated with improved PFS. Median OS was 8.3 months (95%CI 7.0-9.7) and was significantly longer in females than males (10.7 vs. 6.7; p< 0.001), patients receiving subsequent therapy (12.8 vs. 4.9; p< 0.001) and with MFI>10 (9.7 vs. 6.7; p< 0.001). Patients with SFT had the longest OS (17.4; 95%CI 8.9-26.0), followed by LMS (10.4; 95%CI 8.2-12.7). Multivariate analyses confirm female gender, SFT, and MFI>10 to be associated with improved OS. Patients who required dose interruption or dose reduction had significantly longer PFS (5.9 vs. 2.7 months; p< 0.001) and OS (11.7 vs. 6.5; p< 0.001), but this could be associated with longer exposition to the drug.

Conclusion: In our cohort, pazopanib showed modest activity in the majority of STS with a median PFS shorter than in the pivotal trial. SFT showed exceptionally long PFS, longer than in dedicated clinical trials. Moreover, synovial sarcoma and DSRCT seem to be most sensitive to pazopanib. Besides histology, gender and MFI are the only factors associated with PFS and OS. Importantly, pazopanib is associated with significant toxicities and a large proportion of patients required dose adjustments or interruptions. Our results highlighted the need for new therapies in STS.