(P 416) TRIPLR COMNINATION THERAPY IN THE FIRST-LINE TREATMENT OF SOFT TISSUE SARCOMA WITH HIGH TUMOR BURDEN: INTERIM ANALYSIS FROM ALTER-S007 STUDY

Objective: Although single-agent anthracycline drugs are the standard first-line treatment, the objective response rate (ORR) and progression-free survival (PFS) are not satisfactory. While the combination with ifosfamide improves tumor shrinkage rates and PFS, the adverse events of combined chemotherapy are significant, and there is no real improvement in overall survival (OS). Tyrosine kinase inhibitors(TKIs) combined with PD-1 inhibitors may overcome the efficacy shortcomings of single-agent epirubicin by reshaping the immune microenvironment, potentially changing the inherent pattern of current first-line treatments.

Methods: This ongoing phase I/II, open-lable trial(ChiCTR2100048014) enrolled patients (pts) aged 16-75 years old with pathologically confirmed metastatic or unresectable locally advanced STS. Pathologic types are moderately sensitive or above to anthracycline chemotherapy. Pts who met the inclusion criteria were treated with phase I dose results ( E 60 mg/m2 + A 10 mg and P 200 mg；E: IV, D1-3, Q3W, A: PO, QD, D1-14, Q3W, P: IV, Q3W, 2022 ESMO) for a total of 6 treatment cycles (3 weeks each). A+P was maintained for 2 years until progressive disease or unacceptable toxicity. The primary endpoint was PFS and secondary endpoints were ORR, DCR(disease control), OS, 2-year OS and PFSR at 3 and 6 months. Target enrollment of 42 evaluable pts in phase II provided 80% power (two-sided a = 0.1) to distinguish between a null hypothesis of 4.6 months PFS & alternative hypothesis of 7.5 months PFS by log-rank test. Pts used experimental drug at least once will be included in the Full Analysis Set (FAS), and who have completed more than 6 weeks (including 6 weeks) & meet the trial protocol will be included in the Per-protocol Set (PPS).The study also explored possible efficacy prediction biomarkers.

Results: From September 2021 to May 2023, 50 pts (27 males and 23 females) were enrolled (8 pts in phase I and 42 pts in phase II), predominantly with DDLPS (50%). The median age of all is 58 (range 29-73) years old and most pts had a high tumor burden with the median target lesion longest diameter was 75.0 mm(13.2-223.0). At the cut off date on June 2024, median follow-up time was 17.51 months[95%CI 14.78-20.30]. In all pts, the median PFS was 10.58 months [95%CI 8.05, 15.38] in FAS (n=50) and 11.17 months [95%CI 8.87, 17.12] in PPS(n=46), which has exceeded the predefined endpoint. The median OS was not reached, and the OS at 18 months were 66.93% (FAS) and 71.33% (PPS), with the longest OS was 31.5 months. The ORR were 26% and 28.26% in FAS and PPS respectively (table). Among the 13 pts who achieved CR or PR, the median PFS was not reached. Among the 25 pts with DDLPS, the ORR was 20% (FAS, n=25) and 22.73% (PPS, n=22), the median PFS was 10.55 months [95% CI 6.77, NE] and 11.17 months [95% CI 6.93, NE] in FAS and PPS respectively , the median OS was not reached. Safety profile indicated that 22 pts (44%) experienced ≥ grade 3 treatment-related adverse events (TRAEs), and 9 pts(18%) experienced serious adverse events (SAEs).The efficacy analysis indicates that there is no significant correlation between the expression levels of PD-L1(CPS≥1 or not ) and therapeutic outcomes.

Conclusion: Even for late-stage STS pts with high tumor burden, the combination of epirubicin with anlotinib and penpulimab can prolong PFS time, and adverse events were tolerable. For pts achieving CR or PR, the PFS benefit was particularly significant. Most pts with DDLPS, which is relatively insensitive to chemotherapy, achieved significant tumor shrinkage. It is worth further exploring relevant biomarkers to guide future clinical practice. Currently, there are 14 pts showing long-term benefits in ongoing treatment, indicating the existence of a subgroup that derives prolonged benefits.