On that study what we tried to do was to evaluate TMB, tumour mutational burden, as measured in the tumour tissue as a potential prognostic and as a potential predictive marker. That means what is the influence of the tumour mutational burden of your tumour on your outcome when you’re treated with chemo or with chemo-IO, this is the prognostic value, but secondly, also very important, is every single patient treated with chemo plus pembrolizumab benefitting from this therapy or is there any specific subset which is benefitting the most related to TMB? Is there any specific subset that is not benefitting at all? This is the type of analysis we have performed.

I have to say that it was a pre-specified analysis and the analysis was done on a number of patients that had enough samples from four randomised trials, two phase II, KEYNOTE-021C and -021D, and two phase III, KEYNOTE-189 and KEYNOTE-407. So, among those patients with material enough to be analysed we performed whole exome sequencing and then divided patients with tumour mutational burden high, more than 175 mutations, as compared to low, lower than 175 mutations per exome. Of those patients there were roughly a bit more than 50% of the patients actually included into the trial where we got a TMB value. So we analysed what is the impact of TMB on response, PFS and overall survival on the chemotherapy arms but also on the chemotherapy plus pembrolizumab arms and we did not see any significant effect. So those patients treated with chemo or treated with chemo plus IO did the same, regardless of whether they had high tumour mutational burden or low.

The second analysis was if there was any interaction between TMB and outcome of patients treated with chemo or chemo-IO as it was known. So the benefit from chemo-IO was observed in all patients, among those treated with chemo-IO but also in those patients treated with chemo alone. TMB is not an effective marker based on this data to select which patients should not be treated or who should be treated with pembrolizumab plus chemo.

The inference is, based on this analysis, every patient would be a candidate to benefit from pembrolizumab plus chemotherapy.