(P 346) SURROGATE ENDPOINTS FOR OVERALL SURVIVAL IN ADVANCED SOFT TISSUE SARCOMA TRIALS: A SYSTEMATIC REVIEW AND META-ANALYSIS

Objective: Randomized controlled trials (RCTs) are the gold standard assessment of determining if a treatment has an effective outcome by prolonging overall survival (OS). The assessment of OS requires large patient numbers and prolonged follow-up. Given these challenges, alternate endpoints are used as a surrogate for OS to allow a more rapid measure of treatment efficacy. These include progression free survival (PFS), 3-month progression free survival (3moPFS), 6-month progression free survival (6moPFS) and overall response rates (ORR). However, the use of these surrogate endpoints remain controversial. In soft tissue sarcoma (STS) RCTs, intermediate endpoints are increasingly used as primary endpoint. Our objective is to perform a systemic review of RCTs in patients with advanced STS and complete a meta-analysis to evaluate the surrogacy of these alternate endpoints for OS.

Methods: A systemic search of Medline, Embase, Clarivate WoS and Cochrane Central Register of Controlled Trials for RCTs in adults with advanced STS, published between Jan 1946 to Dec 2024, was performed. Non-randomised and non-comparative trials, trials including bone/Kaposi sarcoma, GIST, reviews and meta-analyses were excluded. The relationship between surrogate endpoints and overall survival (OS) was evaluated using weighted linear regression, comparing the HR for OS with the HR for PFS and the odds ratio for ORR, 3moPFS, and 6moPFS. The coefficient of determination (R2) was used to measure the strength of the association, R2 >0.8 signifies strong surrogacy. Surrogate endpoints were only included in the analysis if available. PFS was only included if the HR was available.

Results: Of 10,062 articles, 59 trials (comprising 12,471 patients) met the inclusion criteria. Of these, 42 trials included any STS and 17 included specific subtypes. Phase II design represented 29 trials, 27 Phase III trials and 3 were not documented. Trials the first line setting represented 29 trials.

Conclusion: Of all the surrogate endpoints utilized in STS RCT, PFS correlates best with OS. However, this trial level analysis showed weak correlation for all surrogate endpoints when compared to OS. Despite the limitations of relatively small number of studies and heterogenous population, OS should remain the primary endpoint in STS RCTs, especially in a registration/phase III trial setting. This study highlights the urgent need to identify a true surrogate endpoint for OS, if any, by examining patient level data of identified trials in this study.

Results