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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.
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.
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.
Shares Matthew D. Hellmann, Tumour mutational burden testing, PD-L1 TPS (tumour proportion score), TMB-high (tumour mutational burden >= 10 mutations per megabase).
Shares Tumour mutational burden testing, TMB-high (tumour mutational burden >= 10 mutations per megabase), Neoantigen, The cancer-immunity cycle.
Shares Tumour mutational burden testing, TMB-high (tumour mutational burden >= 10 mutations per megabase), The cancer-immunity cycle, Tumour mutational burden (TMB).
Shares Tumour mutational burden testing, PD-L1 TPS (tumour proportion score), TMB-high (tumour mutational burden >= 10 mutations per megabase), The cancer-immunity cycle.
Shares Tumour mutational burden testing, TMB-high (tumour mutational burden >= 10 mutations per megabase), The cancer-immunity cycle, Tumour mutational burden (TMB).
Shares Tumour mutational burden testing, TMB-high (tumour mutational burden >= 10 mutations per megabase), Tumour mutational burden (TMB), PD-1 / PD-L1 immune checkpoint & T-cell activation.
Shares TMB-high (tumour mutational burden >= 10 mutations per megabase), Tumour mutational burden (TMB), PD-1 / PD-L1 immune checkpoint & T-cell activation, PD-L1.
Shares Hot vs cold tumours, Dana-Farber Brigham Cancer Center, PD-1 / PD-L1 immune checkpoint & T-cell activation, Memorial Sloan Kettering Cancer Center.