Progression-Free and Overall Survival of First-Line Treatments for Advanced Renal Cell Carcinoma: Indirect Comparison of Six Combination Regimens

SIMPLE SUMMARY: Recently, numerous treatments sharing similar mechanisms of action have been approved for advanced renal cell carcinoma. These combinations prolong survival compared to sunitinib, which was previously considered the standard of care in this context. Head-to-head comparisons between these innovative treatments are not available, but this information is needed to guide medical oncologists’ choices. To compare these combination therapies with one another and with sunitinib, our study used an innovative method (the Shiny method) that reconstructs individual patient data from published clinical trials. Using this approach, we demonstrated that pembrolizumab + lenvatinib is the most effective treatment in terms of progression-free survival (PFS) and overall survival (OS). Pembrolizumab + axitinib, nivolumab + cabozantinib and nivolumab + ipilimumab were similar in terms of PFS and superior to sunitinib, but pembrolizumab + axitinib also demonstrated a better OS. Our subgroup analysis showed that in favorable-risk patients, combination therapies showed no significant advantage over sunitinib, while in intermediate-poor risk patients, both pembrolizumab + axitinib and nivolumab + ipilimumab improved OS compared to sunitinib. ABSTRACT: Background: Recently, numerous combination therapies based on immune checkpoint inhibitors (ICI) and vascular endothelial growth factor (VEGF) inhibitors have been proposed as first-line treatments for advanced renal cell carcinoma (aRCC). Our study aimed to compare the efficacy of these combination regimens by the application of an innovative method that reconstructs individual patient data. Methods: Six phase III studies describing different combination regimens for aRCC were selected. Individual patient data were reconstructed from Kaplan–Meier (KM) curves through the “Shiny method”. Overall survival (OS) and progression-free survival (PFS) were compared among combination treatments and sunitinib. Results were summarized as multi-treatment KM curves. Standard statistical testing was used, including hazard ratio and likelihood ratio tests for heterogeneity. Results: In the overall population of aRCC patients, pembrolizumab + lenvatinib showed the longest median PFS and was expected to determine the longest OS. Pembrolizumab + axitinib, nivolumab + cabozantinib and nivolumab + ipilimumab were similar in terms of PFS, but pembrolizumab + axitinib also demonstrated a better OS. Our subgroup analysis showed that sunitinib is still a valuable option, whereas, in intermediate-poor risk patients, pembrolizumab + axitinib and nivolumab + ipilimumab significantly improve OS compared to sunitinib. Conclusion: The Shiny method allowed us to perform all head-to-head indirect comparisons between these agents in a context in which “real” comparative trials have not been performed.