Nivolumab vs Ipilimumab

## Overview

Nivolumab and ipilimumab target different immune checkpoints: nivolumab blocks PD-1 (peripheral tolerance), while ipilimumab blocks CTLA-4 (central tolerance). They are often combined precisely because of their complementary mechanisms. As monotherapies, they differ substantially in efficacy, toxicity, and indication profile.

## Mechanism of Action

Nivolumab: anti-PD-1, blocks peripheral T-cell exhaustion in the tumor microenvironment. Ipilimumab: anti-CTLA-4, removes co-inhibitory braking of T-cell activation at the priming phase in lymph nodes. CTLA-4 blockade increases T-cell activation broadly, while PD-1 blockade preferentially restores exhausted tumor-infiltrating T cells.

## Pharmacokinetics

Ipilimumab: 3 mg/kg or 1 mg/kg q3w (induction), half-life ~14.7 days. Nivolumab: q2–6w, half-life ~27 days. Combination nivo+ipi dosing is now extensively studied.

## Immune-Related Adverse Events

Ipilimumab monotherapy has higher irAE rates than nivolumab monotherapy, particularly severe colitis (grade 3–4: ~15–20% for ipilimumab vs. ~1–2% for nivolumab). Combination nivo+ipi has the highest irAE rates (~59% any grade, ~28% grade 3–4).

## Clinical Evidence

In metastatic melanoma, ipilimumab monotherapy (MDX010-20) showed OS benefit vs gp100 — establishing checkpoint inhibition in melanoma. Nivolumab monotherapy (CheckMate 066) showed superior OS vs DTIC. Nivo+ipi (CheckMate 067): superior PFS and OS over either monotherapy alone.

## Key Takeaways

- Nivolumab: anti-PD-1, lower irAE rate, broader indications as monotherapy
- Ipilimumab: anti-CTLA-4, historically higher irAE rates, rarely used as monotherapy now
- Best used in combination (nivo+ipi), which is superior to monotherapy for eligible patients