pembrolizumab

Overview

Humanized anti-PD-1 immune checkpoint inhibitor with tumor-agnostic TMB-H approval.

Evidence in the corpus

  • One TMB-H ovarian germ cell tumor with squamous transformation (42.1 mut/Mb) achieved a complete response to pembrolizumab, ongoing at 34 months PMID:36862133.
  • The Make-an-IMPACT authors suggest tumor-agnostic immunotherapy with pembrolizumab may benefit rare TMB-H GCTs with squamous transformation PMID:36862133.
  • Pembrolizumab combined with trastuzumab, capecitabine, and oxaliplatin (PTC) in HER2-positive metastatic esophagogastric cancer (phase II, n=37): median PFS 13 months, median OS 27 months, ORR 89%; early ctDNA clearance by 9 weeks (HR 0.18, P=0.001) and intense 89Zr-trastuzumab PET avidity predict durable benefit PMID:37406106.
  • In 177 cervical cancers, TMB-H (13%) and MSI-H (3%) tumor fractions are eligible for pembrolizumab per FDA tumor-agnostic approval; ORR with single-agent PD-1 blockade remains ~10–15% in this setting PMID:37643132.
  • In endometrial carcinoma, Black patients are significantly less likely to harbor MSI-H or TMB-H tumors (15% vs 33% and 14% vs 25% respectively), reducing pembrolizumab eligibility among Black patients PMID:37651310.
  • Among 3 GNH diffuse pleural mesothelioma patients treated with pembrolizumab, 2 achieved partial response (67%) vs. 1/44 (2%) in non-GNH patients, suggesting GNH as a potential ICB response biomarker PMID:38630790.
  • Mismatch repair deficiency in treatment-refractory pituitary neuroendocrine tumors may render them responsive to pembrolizumab; dramatic responses have been reported in this context PMID:38758238.
  • In MSI-H/dMMR prostate cancer (n=27 treated with ICB), pembrolizumab achieved 45% RECIST response rate and 65% PSA50 response; TMB-H/MSS patients showed 0% RECIST responses, suggesting TMB-H alone is insufficient for ICB selection in prostate cancer PMID:38949888.
  • In MSK-CHORD NSCLC, PDL1+ vs PDL1− patients on immunotherapy had OS HR=0.64 (95% CI 0.54–0.77, P<0.001) in 754 patients, validating at scale the same magnitude seen in the smaller MSK-BPC cohort (HR=0.58, n=29). The PDL1 biomarker practice for pembrolizumab selection in NSCLC was supported at population scale. PMID:39506116
  • MSI-H / dMMR tumors are the primary FDA tumor-agnostic indication for pembrolizumab; MiMSI (deep-learning MSI classifier) recovers cases that MSISensor miscalls due to low tumor purity (sensitivity 91.6% vs 86.1%), directly expanding the pool of pembrolizumab-eligible patients identified through routine NGS. PMID:39746944
  • In metastatic urothelial carcinoma (mUC), despite supplantation of platinum chemotherapy by enfortumab-vedotin + pembrolizumab as the first-line standard, gemcitabine/cisplatin remains relevant as second-line therapy after EV+pembrolizumab. Pretreatment cfDNA features (PIK3CA, ERBB2, TERT, ctDNA VAF) are positioned as prognostic biomarkers for patients receiving pembrolizumab-containing or chemotherapy regimens. PMID:40256659
  • In a paired primary-metastasis WES/cfDNA study of bladder cancer (n=60), ARID1A mutations were identified as late-arising, metastasis-enriched alterations (28% metastatic vs 14% low-grade non-invasive) that may serve as biomarkers for immune checkpoint inhibitor (including pembrolizumab) sensitivity and EZH2 inhibitor sensitivity; direct pembrolizumab outcomes were not reported PMID:36543146
  • 9 of 12 metastatic gallbladder carcinoma patients receiving immune checkpoint inhibitors received pembrolizumab; 42% (5/12) showed evidence of response including 3 MSI-High, 1 MSS/TMB-high, and 1 MSS/TMB-low tumor PMID:36228155
  • Lenvatinib+pembrolizumab combination data were not available in the HiTME training cohorts; cited as a limitation for the ccRCC IO/TKI decision-tree model PMID:22138691
  • KEYNOTE-224 in HCC: pembrolizumab ORR 16.3% in 104 patients, median OS 12.9 months (second-line, post-sorafenib); FDA approved (tumour-agnostic) for MSI-H/dMMR HCC (~3% of HCCs); PD-L1 IHC does not predict response in HCC PMID:24798001
  • Investigational anti-PD-1 ICI for recurrent/metastatic NPC; listed among PD-1/PD-L1 antibodies under evaluation alongside toripalimab, penpulimab, sintilimab, and nivolumab; monotherapy ORR approximately 15–20% in NPC PMID:24952746
  • Anti-PD-1 efficacy in biliary tract cancer (BTC) is noted to be modulated by gut microbiota composition; Bacteroidetes enrichment correlates with improved outcomes while Proteobacteria dominance reduces efficacy PMID:25608663
  • Nonsynonymous tumor mutation burden (TMB) predicted durable clinical benefit (DCB) on pembrolizumab in NSCLC (median 302 vs 148 mutations in DCB vs NDB, Mann-Whitney P=0.02); a candidate cutoff of ≥178 nonsynonymous mutations distinguished responders with 73% DCB vs 13% in the discovery cohort PMID:25765070
  • 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 melanoma cases) contextualize pembrolizumab biomarker hypotheses; Immune-subclass survival advantage and LCK/LScore bivariate model proposed as predictive framework PMID:26091043
  • Hugo et al. (n=38 metastatic melanoma): pembrolizumab (and nivolumab) anti-PD-1 therapy; overall mutational load associated with survival but not response (P=0.30); BRCA2 LOF mutations enriched 6× in responders (28% vs 6%, Fisher P=0.002, OR=6.2); IPRES transcriptional program (mesenchymal transition, angiogenesis, ECM remodeling) defined innate non-responders (9/13 NR vs 1/15 R); IPRES overlaps MAPKi-induced signatures, implicating vemurafenib/dabrafenib/trametinib sequencing as potential resistance driver PMID:26997480
  • PD-1 checkpoint inhibitor; KEYNOTE-042 and KEYNOTE-024 subgroup analyses showed comparable survival benefit across age cut-off of 65 in NSCLC; largest absolute 2-year survival gain post-2011 was in patients <55 years (37.7% to 50.3%) PMID:27346245
  • Used as anti-PD-1 immune checkpoint blockade in acral lentiginous melanoma (ALM); 2 of 3 complete responders were anti-PD-1-treated but had low mutational burden (<75 coding mutations), suggesting response in ALM may occur via mechanisms distinct from mutational load PMID:28373299.
  • In whole-exome sequencing of 63 clear cell endometrial carcinomas (UCCC), 11.3% were MSI-high; the authors cite two MSI-H EC patients with clinical responses to pembrolizumab in a phase 2 trial of mismatch-repair-deficient tumors as motivation for immunotherapy evaluation in CCEC. PMID:28485815
  • Authors cite the SARC028 trial showing 40% response to a PD-1 inhibitor in UPS and propose that MFS — molecularly indistinguishable from UPS — should be added to checkpoint-inhibitor trials evaluating pembrolizumab; STLMS has the highest PD-L1 expression among sarcoma types (significantly higher than ULMS, p=4e-5) PMID:29100075
  • Reflex MSI testing and pembrolizumab (FDA-approved for MSI-H tumors) are recommended as standard practice in metastatic EGC; MSI-H patients had median PFS 4.8 months on first-line chemotherapy vs multiple durable immunotherapy responses; high TMB (>9.7 mut/Mb) was associated with median OS 16.8 vs 6.62 months on immunotherapy (HR=0.40, P=0.058) PMID:29122777
  • FDA approval of pembrolizumab for MSI-H solid tumours renders all 99 MSI-H/hypermutated CRCs in this 1,134-sample MSK-IMPACT cohort (8.7% of total) eligible per OncoKB Level 1 actionability; overall actionability rate was 86% in MSI-H vs 37% in MSS mCRC PMID:29316426
  • One of the anti-PD-(L)1 agents in the 240-patient MSK NSCLC cohort; TMB above the 50th percentile predicted durable clinical benefit (DCB 38.6% vs 25.1%, p=0.009) and combining high TMB with PD-L1 >=1% raised DCB rate to 50% PMID:29337640

Resistance mechanisms

  • IPRES (Innate anti-PD-1 Resistance) transcriptional program — a co-regulated set of 26 signatures covering mesenchymal transition, ECM remodeling, angiogenesis, hypoxia, and wound healing — was enriched in 9/13 non-responders vs 1/15 responders in pretreatment melanoma biopsies; overlaps substantially with MAPK-inhibitor-induced transcriptional programs, implicating prior vemurafenib/dabrafenib/trametinib as a potential cross-resistance driver PMID:26997480.

Cancer types (linked)

Sources

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  • PMID:28373299
  • PMID:28485815 — Le Gallo et al. 2017, Oncotarget. Whole-exome sequencing of 63 CCECs; 11.3% MSI-H; pembrolizumab cited as clinically active in MSI-H EC.

This page was processed by entity-page-writer on 2026-05-15. - PMID:29100075

This page was processed by wiki-cli on 2026-05-15. - PMID:29122777

This page was processed by wiki-cli on 2026-05-15. - PMID:29316426

This page was processed by wiki-cli on 2026-05-15. - PMID:29337640

This page was processed by entity-page-writer on 2026-05-15.