Revisiting the role of immune checkpoint inhibitor–based combination therapies in favorable risk metastatic renal cell carcinoma: An updated pairwise and network meta-analysis of long-term survival outcomes.

Abstract

e16504 Background: The benefit of immune checkpoint inhibitor (ICI)–based combination therapy in IMDC favorable risk metastatic renal cell carcinoma (mRCC) remains uncertain, with persistent concerns regarding potential overtreatment. Favorable risk mRCC typically follows an indolent disease course with delayed mortality events, underscoring the need for an updated meta-analysis incorporating extended follow-up survival data to accurately assess the long-term efficacy of these regimens in this population. Methods: We systematically searched major bibliographic databases and conference proceedings for recently published phase III randomized trials evaluating ICI-based combination therapies in IMDC favorable risk mRCC, focusing on studies reporting updated and extended follow-up data for progression-free survival (PFS) and overall survival (OS). Both pairwise and network meta-analyses were conducted. Results: Six phase III trials involving 5121 patients (1267 with IMDC favorable risk mRCC) were included. The evaluated regimens comprised ICI plus anti–vascular endothelial growth factor (VEGF) therapies (including VEGF tyrosine kinase inhibitors and anti-VEGF monoclonal antibodies) and dual ICI therapy. In the pairwise meta-analysis, compared with sunitinib, ICI plus anti-VEGF therapy was associated with significantly longer PFS (hazard ratio [HR], 0.68; 95% CI: 0.54-0.79), whereas dual ICI therapy was associated with inferior PFS (HR, 1.76; 95% CI, 1.25-2.48). Neither strategy demonstrated a significant OS benefit, with HRs of 0.97 (95% CI, 0.79-1.19) and 0.82 (95% CI 0.60-1.12), respectively. In the network meta-analysis, pembrolizumab-lenvatinib and nivolumab-cabozantinib showed significant PFS improvements versus sunitinib, with HRs of 0.50 (95% CI, 0.35-0.71) and 0.67 (95% CI, 0.46-0.97), ranking first and second with P-score of 0.94 and 0.67, respectively. Network comparisons using dual ICI therapy as the reference showed significantly longer PFS with all ICI-based anti-VEGF regimens and sunitinib. No ICI-based combination regimen demonstrated a significant OS advantage over sunitinib, although P-score–based ranking suggested a numerical preference for avelumab–axitinib and nivolumab–ipilimumab. Conclusions: Leveraging extended follow-up survival data, this meta-analysis indicates that ICI-based combination therapies do not confer a clear OS benefit over sunitinib in IMDC favorable risk mRCC, calling into question the routine use of intensified upfront therapy in this population. While certain ICI plus anti-VEGF regimens demonstrated improvements in PFS, dual ICI therapy was associated with inferior PFS. These findings favor selective, risk-adapted therapy over routine intensification in indolent disease.