Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy.
Razvan CristescuRobin MoggMark AyersAndrew AlbrightErin MurphyJennifer YearleyXinwei SherXiao Qiao LiuHongchao LuMichael NebozhynChunsheng ZhangJared K LuncefordAndrew JoeJonathan ChengAndrea L WebberNageatte IbrahimElizabeth R PlimackPatrick A OttTanguy Y SeiwertAntoni RibasTerrill K McClanahanJoanne E TomassiniAndrey LobodaDavid KaufmanPublished in: Science (New York, N.Y.) (2018)
Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) checkpoint blockade immunotherapy elicits durable antitumor effects in multiple cancers, yet not all patients respond. We report the evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials. Tumor mutational burden (TMB) and a T cell-inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab. TMB and GEP were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology. These biomarkers may have utility in clinical trial design by guiding rational selection of anti-PD-1 monotherapy and combination immunotherapy regimens.
Keyphrases
- clinical trial
- dna damage
- phase ii
- end stage renal disease
- open label
- cell cycle
- ejection fraction
- newly diagnosed
- single cell
- copy number
- genome wide
- emergency department
- prognostic factors
- randomized controlled trial
- study protocol
- advanced non small cell lung cancer
- small molecule
- cell proliferation
- double blind
- phase iii
- young adults
- squamous cell
- risk factors
- binding protein
- transcription factor