Indirect Comparisons via Sorafenib for the Comparative Effectiveness of Two PD-1/PD-L1 Inhibitors to Treat Advanced Hepatocellular Carcinoma Patients without Prior Systemic Therapies

Abstract

Introduction: Advanced hepatocellular carcinoma (HCC) represents a major public health threat. Several emerging combination therapies have shown promising results for the first-line treatment of advanced HCC. The present study compared the efficacy of atezolizumab plus bevacizumab (AB) with lenvatinib plus pembrolizumab (LP), which were two of the leading combination therapies.

Methods: The outcomes of the present analysis were overall survival (OS) time and progression-free survival (PFS) time. Two matching-adjusted indirect comparisons (MAICs) were first conducted using the individual-level patient data (IPD) of the sorafenib arm from a previous clinical trial and the aggregate data (AgD) of the AB and LP arms from the corresponding published trials. From the MAICs, the hazard ratios (HRs) of AB and LP vs sorafenib were estimated by conducting weighted Cox regressions. The HRs from the two MAICs were then pooled to conduct a second-order indirect comparison of AB vs LP.

Results: In the MAIC analyses, AB had better efficacy on both OS (HR: 0.58, 95% CI: 0.42-0.79) and PFS (HR: 0.59, 95% CI: 0.47-0.76) than sorafenib, whereas LP had significantly better efficacy on PFS (HR: 0.62, 95% CI: 0.41-0.94) but not OS (HR: 0.83, 95% CI: 0.52-1.32). In the second-order comparison, AB was insignificantly more efficacious on OS (HR: 0.71, 95% CI: 0.42-1.23) than and similarly efficacious on PFS (HR: 0.95, 95% CI: 0.60-1.51) as the LP regimen.

Conclusion: LP regimen may be a potential first-line immunotherapy option for advanced HCC given its comparative effectiveness in relation to AB.

Keywords: PD-1; PD-L1; adjusted; balancing; first-line; matching; overall; progression-free; survival; unresectable.

Figure 1

Flowchart of matching-adjusted indirect comparisons (MAIC), the validation of the MAIC method, and the second-order indirect comparison.

Figure 2

The kernel density of the entropy balancing weights of individual-level patients (IPD) in the sorafenib arm when balanced to the atezolizumab plus bevacizumab (AB) arm and the lenvatinib plus pembrolizumab (LP) arm. The deviation and dispersion of each line from the black vertical line demonstrate the unbalance of sorafenib IPD and the aggregate data of the corresponding comparator regimen before entropy balancing. The dissimilarity of the two lines of entropy balancing weights represents the unbalance between the aggregate data of the AB and LP arms.