# Survival Assessment by Central Review vs. Local Investigator in Metastatic Melanoma: A Systematic Review and Meta-Analysis

## TL;DR

This study compares survival assessments by local investigators and central review in melanoma trials, finding strong agreement and suggesting local assessments are reliable for most cases.

## Contribution

The study provides evidence that local investigator assessments of progression-free survival are as reliable as blinded central review in cutaneous melanoma trials.

## Key findings

- Strong agreement between local investigator and central review assessments of progression-free survival in cutaneous melanoma trials.
- Discrepancies between assessment methods were small and rarely changed trial conclusions.
- The overall combined discrepancy index was 1.08, indicating a statistically significant but numerically small difference.

## Abstract

There is a need to investigate the optimal endpoints and clinical trial designs that may be best suited to accelerate progress in immunooncology drug development. In this study, we were interested in assessing the endpoint of progression-free survival (PFS) as assessed by blinded independent central review (BICR), and of that assessed by local investigators (LI) in randomized clinical trials (RCTs). This study was developed to analyze the discrepancy indexes (DIs) to evaluate differences between PFS assessments by LIs and BICR in RCTs of patients with metastatic melanoma. This systematic review and meta-analysis of 12 RCTs (11 in cutaneous melanoma and one uveal) included 4915 participants. In this systematic review and meta-analysis of 12 randomized trials including 4915 patients, we found strong agreement between LI- and BICR-assessed PFS, particularly in cutaneous melanoma. Differences between the two assessment methods were small and rarely changed trial conclusions. These findings support the use of LI-assessed PFS as a reliable primary endpoint in most cutaneous melanoma trials, with BICR reserved for selected situations where assessment uncertainty is higher.

Background: Although blinded independent central review (BICR) can reduce assessment variability, it introduces additional financial and logistical burdens to trial operations. This study analyzed the discrepancy indexes (DIs) to evaluate differences between progression-free survival (PFS) assessments by local investigators (LIs) and BICR in randomized clinical trials (RCTs) of patients with metastatic melanoma. Methods: A comprehensive literature search was conducted on PubMed, Embase, and Cochrane databases up to 30 June 2024. The primary outcome was the DI, which was calculated for each trial as a ratio of the hazard ratios (HR)BICR by HRLI. The agreement between PFS HRs was also evaluated using the intraclass correlation coefficient (ICC) and Pearson’s correlation coefficient (r). Results: Twelve studies comprising 4915 patients were included in this study. Of these, 10 (83%) were Phase III, 11 (92%) were cutaneous melanoma, one was uveal, and all identified PFS as the primary endpoint. Most (86%) of the PFS comparisons yielded the same statistical inference by both BICR and LIs. The overall combined DI was calculated at 1.08 (95% CI: 1.01–1.15), indicating a statistically significant, numerically small difference in PFS evaluations driven primarily by the uveal Phase III double-blinded study, while there was a strong overall correlation [(ICC: 0.87, p < 0.001); (r = 0.89, 95% CI 0.67–0.96, p < 0.0001)]. Cutaneous melanoma trials demonstrated strong agreement between BICR and local investigator assessments. Conclusions: In randomized trials of metastatic cutaneous melanoma, LI-assessed PFS closely aligns with BICR and provides equivalent trial-level conclusions in most cases. These findings support the use of LI-assessed PFS as a valid and practical primary endpoint, without routine requirement for BICR. Central review should be reserved for selected scenarios.