Introduction:

Immune checkpoint inhibitor (ICI)–based combination therapies have transformed first-line treatment of metastatic renal cell carcinoma (mRCC). While hazard ratios (HRs) demonstrate statistical superiority over sunitinib, this metric often fails to convey the absolute magnitude and clinical relevance of survival benefit. Restricted mean survival time (RMST) offers a more intuitive and interpretable alternative by quantifying average survival over a fixed time horizon. We conducted a comparative effectiveness analysis using RMST to evaluate survival gains across ICI combinations and contextualized these benefits by calculating treatment cost and toxicity burden per month of survival gained.

Methods:

Four Phase III trials—CLEAR, CheckMate 214, CheckMate 9ER, and KEYNOTE-426—were selected based on current guideline recommendations. Overall survival (OS) and progression-free survival (PFS) data were reconstructed from published Kaplan–Meier curves, and restricted mean survival time (RMST) was calculated using a 42-month truncation point. Absolute survival gain was assessed as the difference in RMST (dRMST) between treatment arms. Drug cost, grade ≥3 adverse events (AEs), and high-dose corticosteroid (HDS) use were normalized per RMST month gained.

Results:

Compared with sunitinib, OS dRMST was 4.15 months (95% CI: 1.86–6.45, p<0.001) for Nivolumab + Cabozantinib (NIVO–CABO), 3.53 (1.43–5.62, p=0.001) for Lenvatinib + Pembrolizumab (LEN–PEM), 2.75 (0.97–4.53, p=0.002) for Nivolumab + Ipilimumab (NIVO–IPI), and 2.68 (0.77–4.58, p=0.005) for Pembrolizumab + Axitinib (PEM–AXI). PFS gains were 10.07 (LEN–PEM), 6.49 (NIVO–CABO), 4.39 (PEM–AXI), and 1.44 months (NIVO–IPI) (Table 1). OS cost per month gained ranged from $49,952.77 (NIVO–IPI) to $284,944.36 (LEN–PEM); PFS cost ranged from $50,679.52 (NIVO–IPI) to $109,596.00 (PEM–AXI). Grade ≥3 AE increases per OS month gained ranged from 0–4%. HDS use per OS month gained was 10% (NIVO–IPI), 5% (PEM–AXI, NIVO–CABO), and 4% (LEN–PEM); per PFS month gained, rates were 20%, 3%, 3%, and 1%, respectively (Figure 1).

Conclusion:

RMST-based analysis enables nuanced comparison of ICI regimens in mRCC, highlighting modest OS benefit, greater PFS separation, cost differences, and distinct toxicity burdens. Nivolumab + Cabozantinib demonstrated the greatest OS benefit, while Lenvatinib + Pembrolizumab achieved the highest PFS gain. These findings underscore the importance of integrating multiple treatment attributes—beyond hazard ratios—into personalized treatment decision-making.

Funding: N/A