Medicine Matters oncology

There's are some very exciting data at ESMO 2020 looking at the biomarker component of the Javelin 100 study. Just to recap on the Javelin 100 study, it's a randomized phase III trial of maintenance avelumab sequenced with frontline chemotherapy in metastatic urothelial cancer. The trial had a hazard ratio for survival in the ITT population of 0.69, which is a significant survival advantage. The work we're presenting here performs whole exome sequencing, RNA sequencing, and immunohistochemistry exploring biomarkers associated with response.

There are three or four major findings. The first major finding is it appears both the immune component and the tumor component of PD-L1 expression are associated with enrichment. You'll be aware that some biomarker programs focus on tumor cell expression of PD-L1, other biomarker programs focus on immune component of PD-L1 in other settings. This is important, because for biomarker development in the future, we may need to use both to maximize outcomes.

The second major finding is around tumor mutational burden. And we can show that patients with high TMB, and that's high tumor complexity, have a better outcome with avelumab than low TMB. And actually, it appears to be somewhat predictive, but when you combine TMB with PD-L1, you can show actually both are relevant. And so neither TMB or PD-L1 are able to identify all of the winners.

The third major finding is around the mutational analysis. And what we can see on mutational analysis associated with, you know, the high TMB piece is that, actually, the type of mutation and the location of the mutation may be relevant in predicting outcomes. So it's not just TMB. The actual type and location of the mutation may be relevant. Gene expression analysis showed a series of immune genes associated with response to avelumab which were not associated with response to best supportive care underlying the immune mechanism of the drug.

And then I think the last major part of that is we looked at patients who had high gene expression, immune gene expression, and we identify those patients that didn't do terribly well, those patients developed resistance. So the patients with high gene expression who didn't respond, why didn't they respond? And we could see some signatures that were potentially associated with resistance, and this included not signaling and angiogenesis type signatures.

So in summary, the Javelin 100 trial showed maintenance avelumab was associated with a survival advantage. This biomarker piece shows, firstly, that neither PD-L1 or TMB confined all the responders. The mutational analysis suggests the type and location of mutation is relevant. The gene expression analysis shows broad spectrum of immune genes, both from the innate and the adaptive immune system, associated with response. And then we could also find some mechanisms of potential resistance for exploration in the future, one of which is angiogenesis.