ipilimumab

Overview

Ipilimumab is an anti-CTLA-4 monoclonal antibody immune checkpoint inhibitor with FDA approvals in melanoma, non-small cell lung cancer, renal cell carcinoma, colorectal cancer (MSI-H), and mesothelioma (in combination with nivolumab).

Evidence in the corpus

  • In genomic near-haploidization (GNH) diffuse pleural mesothelioma (DPM), 3 GNH patients treated with ipilimumab/nivolumab or pembrolizumab achieved 2 partial responses (67%), compared with only 1/44 (2%) non-GNH patients PMID:38630790.
  • GNH status (allele-specific copy number analysis showing near-haploid genome) may identify a DPM subset with substantially higher probability of response to dual checkpoint blockade with ipilimumab+nivolumab PMID:38630790.
  • 1 metastatic gallbladder carcinoma patient received ipilimumab/nivolumab combination among 12 ICI-treated patients in the MSK GBC cohort (n=233); 42% (5/12) showed evidence of ICI response including 3 MSI-High patients PMID:36228155
  • Anti-CTLA-4 antibody cited in combination regimens for HCC; CTLA4 is targeted by ipilimumab and tremelimumab in combination strategies for hepatocellular carcinoma PMID:24798001
  • Studied in 59 metastatic melanoma (SKCM) patients; high tumor mutational load was associated with long-term clinical benefit under anti-CTLA-4 blockade (P=0.01 discovery, P=0.009 validation); a shared tetrapeptide neoantigen signature in responders predicted overall survival better than mutational load alone PMID:25409260
  • CD274 (PD-L1) focal amplifications in BRAF-mutant melanoma subtype and high PD-1/PD-L1 expression in Immune transcriptomic subclass (51% of 329 TCGA cases) provide rationale for checkpoint blockade; the authors caution that Immune subtype responsiveness to ipilimumab, pembrolizumab, and nivolumab is unproven in this cohort PMID:26091043
  • In 110 metastatic melanoma (SKCM) patients, high pretreatment nonsynonymous mutational load (P=0.0076) and predicted neoantigen load (P=0.027) were significantly associated with clinical benefit from anti-CTLA-4 blockade; cytolytic activity (GZMA+PRF1, P=0.042) and tumor CTLA4 expression (P=0.033) were each elevated in responders PMID:26359337.
  • Used as immune checkpoint blockade (anti-CTLA-4) in 22 acral lentiginous melanoma (ALM) patients; 3 complete responders to anti-CTLA-4 ± anti-PD-1 had low mutation (<75) and neo-antigen (<60) burdens — opposite of the expected mutation-burden correlation seen in cutaneous melanoma PMID:28373299.
  • In the nivolumab melanoma study, prior ipilimumab exposure (Ipi-P vs Ipi-N) defined distinct biomarker contexts: TMB/clonal load predicted response only in Ipi-N patients; TCR diversity dynamics differed between groups; SERPINB3/B4 mutations previously associated with anti-CTLA-4 benefit showed a non-significant trend toward disease control PMID:29033130
  • Authors advocate considering combination checkpoint blockade with anti-CTLA4 agents including ipilimumab for MSI-H EGC given rapid failure on first-line cytotoxic therapy (median PFS 4.8 months) but durable immunotherapy responses in the MSK-IMPACT cohort PMID:29122777
  • Used as anti-CTLA-4 agent in combination with anti-PD-(L)1 in a subset of the 63-patient ccRCC validation cohort; PBRM1 biallelic LOF was enriched in clinical benefit patients across both mono- and combination-therapy regimens PMID:29301960
  • 14% of the 240-patient MSK NSCLC cohort received PD-(L)1 + ipilimumab combination therapy; high TMB associated with durable clinical benefit across both mono- and combination-therapy arms PMID:29337640

Resistance mechanisms

  • Non-GNH diffuse pleural mesothelioma shows very poor response rates (2%) to ipilimumab/nivolumab or pembrolizumab PMID:38630790.

Cancer types (linked)

Sources

  • PMID:38630790
  • PMID:36228155
  • PMID:26359337 — Van Allen et al. (Science 2015). Genomic correlates of ipilimumab response in 110 metastatic melanoma patients; mutational and neoantigen load as predictive biomarkers.

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