1583P - Trial-level surrogacy of intermediate endpoints in adjuvant or neoadjuvant use of immune checkpoint blockade

Background

Surrogate endpoints (SEPs) are intermediate endpoints that can substitute clinical outcomes such as overall survival (OS). Neoadjuvant or adjuvant immune checkpoint blockade (ICB) may improve survival for patients diagnosed with early cancer disease. Multiple studies evaluating the role of ICB in the curative setting leveraged SEPs to predict treatment efficacy, although few studies sought to evaluate the surrogacy performance of these endpoints. Our meta-analysis aims to investigate whether SEPs can predict outcomes for cancer patients treated with ICB in the curative setting.

Methods

We systematically searched Embase, PubMed, and Cochrane databases up to March 2024 for randomized controlled trials (RCTs) assessing ICBs in the adjuvant or neoadjuvant settings. Studies evaluating adult patients with solid tumours were included. Disease-free survival (HR_DFS), 1-year overall survival (HR_1yr), event-free survival (HR_EFS), and complete pathological responses (pCR) were assessed using SEPs for OS (HR_OS). Statistical analysis included linear regression models weighted by trial sizes. SEPs were categorized based on the coefficient of determination (R²) as follows: R2 ≥ 0.7 will be interpreted as strong correlations, values between 0.69 and 0.5 as moderate correlations, and values < 0.5 as weak correlations.

Results

We included 28 out of 3,233 studies, encompassing 18,754 patients treated with ICB in curative settings. HR_DFS revealed a good association with HR_OS (R² = 0.64; 95% CI, 0.32–0.96), while the HR_1yr demonstrated poor correlation with HR_OS (R²=0.00, 95%CI 0.00-0.03). Similarly, in neoadjuvant ICB (6,938 patients), HR_EFS (R²= 0.34, 95%CI 0.00-0.96) and risk ratio for pCR (R²= 0.04, 95%CI 0.00-0.39) did not exhibit a strong surrogacy performance for HR_OS. Notably, in the subgroup analysis of patients with melanoma, DFS presented a strong correlation with OS (R²= 0.79. 95%CI 0.46-1.00).

Conclusions

Our meta-analysis suggests that SEPs for RCTs evaluating ICB in the curative setting demonstrate limited trial-level surrogacy performance for OS. In studies evaluating adjuvant treatment for pts with melanoma, DFS showed strong surrogacy for OS. Further studies should be conducted to validate the use of SEPs in clinical trial and drug approval process.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.