{"entity":{"id":"paper-ricciuti-tmb-pd-l1-levels-jama-oncol-2022","kind":"paper","name":"Association of high tumor mutation burden in non-small cell lung cancers with increased immune infiltration and improved clinical outcomes of PD-L1 blockade across PD-L1 expression levels","aka":[],"tldr":"Pooling more than fifteen hundred patients showed that the more mutations a lung cancer carries the better immunotherapy works, at every level of the PD-L1 stain, but the best dividing line was about twice the number the licensing authorities use.","summary":"A multicentre cohort study of patients with advanced non-small-cell lung cancer treated with PD-1 or PD-L1 inhibition without chemotherapy, drawn from three datasets, analysed the association between increasing tumour mutation burden and outcomes across clinically relevant PD-L1 levels. Among 1,552 patients, median age 66 years, a regression tree modelling response rate as a function of burden identified two groupings in the discovery cohort, low (19.0 or fewer mutations per megabase) and high (more than 19.0), which were associated with increasing improvements in response, progression-free survival and overall survival in the discovery cohort and in two independent cohorts. These levels were also associated with significant improvements within each PD-L1 subgroup of less than 1%, 1% to 49% and 50% or higher. Response was as high as 57% with high burden and PD-L1 50% or more and as low as 8.7% with low burden and PD-L1 under 1%. Multiplexed immunofluorescence and transcriptomic profiling linked high burden to greater immune infiltration.","asOf":"2026-09-25","links":[{"label":"Ricciuti et al., JAMA Oncol 2022: tumour mutational burden and PD-(L)1 blockade across PD-L1 levels in 1,552 patients","url":"https://doi.org/10.1001/jamaoncol.2022.1981"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/35708671/"}],"tags":[],"related":["tmb-high","pd-l1-tps"],"cancers":["nsclc"],"sections":[],"technologies":["tmb-testing","cgp","checkpoint-inhibitor","single-cell-spatial"],"targets":["pdl1","pd1"],"drugs":[],"companies":[],"institutions":["dana-farber","mskcc"],"pathways":["cancer-immunity-cycle","pd1-checkpoint"],"terms":["tmb","neoantigen","cold-vs-hot"],"trials":[],"people":["matthew-hellmann"],"bottlenecks":[],"keyPapers":[],"journals":["jama-oncology"],"dependsOn":[],"notes":[],"journal":"JAMA Oncology","year":2022,"doi":"10.1001/jamaoncol.2022.1981","pmid":"35708671","authors":"Ricciuti B, Wang X, Alessi JV, et al.","paperType":"observational","findings":["The data-derived threshold was more than 19 mutations per megabase, not 10.","Burden predicted response, progression-free survival and overall survival within every PD-L1 stratum.","Response ranged from 57% with both markers high to 8.7% with both low.","High burden was accompanied by greater immune infiltration on imaging and transcriptomics."],"whatItMeans":"It is the strongest case that mutation burden is real biology in lung cancer and, at the same time, the clearest demonstration that its threshold is not fixed, which is why it never became a reliable selector.","caveats":["Retrospective across three cohorts with different panels and pipelines.","Patients received monotherapy, so the finding does not extend to chemo-immunotherapy.","A threshold found by regression tree in one cohort is at risk of overfitting even when it validates."],"changedPractice":false,"participants":1552},"route":"/key-papers/paper-ricciuti-tmb-pd-l1-levels-jama-oncol-2022/","neighbours":{"biomarker":[{"id":"pd-l1-tps","kind":"biomarker","name":"PD-L1 TPS (tumour proportion score)","route":"/biomarkers/pd-l1-tps/"},{"id":"tmb-high","kind":"biomarker","name":"TMB-high (tumour mutational burden >= 10 mutations per megabase)","route":"/biomarkers/tmb-high/"}],"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"single-cell-spatial","kind":"technology","name":"Single-cell & spatial profiling","route":"/technologies/single-cell-spatial/"},{"id":"tmb-testing","kind":"technology","name":"Tumour mutational burden testing","route":"/technologies/tmb-testing/"}],"target":[{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"},{"id":"pdl1","kind":"target","name":"PD-L1","route":"/targets/pdl1/"}],"institution":[{"id":"dana-farber","kind":"institution","name":"Dana-Farber Brigham Cancer Center","route":"/institutions/dana-farber/"},{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"}],"pathway":[{"id":"pd1-checkpoint","kind":"pathway","name":"PD-1 / PD-L1 immune checkpoint & T-cell activation","route":"/pathways/pd1-checkpoint/"},{"id":"cancer-immunity-cycle","kind":"pathway","name":"The cancer-immunity cycle","route":"/pathways/cancer-immunity-cycle/"}],"term":[{"id":"cold-vs-hot","kind":"term","name":"Hot vs cold tumours","route":"/terms/cold-vs-hot/"},{"id":"neoantigen","kind":"term","name":"Neoantigen","route":"/terms/neoantigen/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"}],"person":[{"id":"matthew-hellmann","kind":"person","name":"Matthew D. Hellmann","route":"/people/matthew-hellmann/"}],"journal":[{"id":"jama-oncology","kind":"journal","name":"JAMA Oncology","route":"/journals/jama-oncology/"}]}}