We are here in the Best of ASCO, Miami, sponsored by the Memorial Cancer Institute to talk about immunotherapy for lung cancer. It’s a very important topic because we have had a lot of developments in the last year regarding immunotherapy. First of all we have now the combination of chemotherapy and immunotherapy as a new standard of care. The FDA recently approved the combination of pembrolizumab with chemotherapy for new patients with stage 4 lung cancer. This was based on a randomised phase II study, for that reason not everybody is embracing this new indication yet because a lot of the physicians are waiting for confirmatory phase III data and I agree with that. I think now we have the option to start a new patient on palliative chemotherapy or the combination of chemotherapy with pembrolizumab and I think it’s very hard to argue in favour or against because, as I said before, the data is only based on phase II randomised data.

We also are very happy because we have other options for the patients. As many of you know, we already have pembrolizumab approved for first line for patients that have more than 50% expression of PD-L1 and that’s another option for new patients with stage 4 lung cancer. The interesting thing about this is that despite the fact that nivolumab was unable to get the same indication and approval we have other checkpoint inhibitors like atezolizumab, durvalumab, avelumab that are on the way to get phase III randomised data. So hopefully soon we’ll have data with all of these drugs to see if they can also get first line indication as a single agent or first line indication in combination with chemotherapy.

Another important development in the area of immunotherapy is the fact that we’re looking for markers, biological markers, that can help us to predict response. Everybody knows about PD-L1 and tumour mutation burden; we know that the higher is the PD-L1 the higher the chance of response. However, we know that it’s not a perfect marker, it’s very controversial, there are a lot of pros and cons with PD-L1 so that’s why the story of PD-L1 hasn’t finished yet. The fact is that the FDA has drugs like atezolizumab and nivolumab approved without PD-L1 staining because patients still respond even if they are PD-L1 negative, that’s why it’s not a perfect marker. With tumour mutation burden we know that the higher the tumour mutation burden the higher the chance of response and now the molecular marker companies are providing tumour mutation burden scores in their results.

We have very interesting potential new markers, one of them is, for example, the microbiome. There are studies presented in ASCO, a very interesting study, retrospective unfortunately only, that if you give antibiotics before you start the patient on immunotherapy the chance of response is less. This is based on the fact that the use of antibiotics destroys the microbiome and the normal flora of the intestine and that probably has to do with immunotherapy. There is more coming about this topic, very exciting new topic.

Also we have postulating new mechanisms of resistance; one of them is a mutation in STK11. Apparently we are very close to confirming that we now have resistant mutations to immunotherapy, something very interesting, and STK11 is one of the potential resistant mutations. The response to immunotherapy in patients that have this mutation is much lower.

Another interesting finding is there is a mechanism of resistance for immunotherapy that is being documented more and more, it’s the beta-carotene pathway. There are five mutations in this pathway and if the patient has one of the mutations probably he’s not going to do very well with immunotherapy. That is why these are all very interesting findings that were presented in ASCO and we’re looking forward to confirmation of all of these in general. We can say also that if the patient has a genetic aberration like EGFR, ALK, ROS1, they probably don’t do well with immunotherapy as the patients have wildtype genes. That’s another confirmatory fact that we saw in ASCO and in many other meetings that probably immunotherapy is not the best choice for patients with genetic aberrations. For example in ASCO there was a study with exon 14 skipping mutation and the patients that had this genetic aberration didn’t do well with immunotherapy, they had a very low response rate, around 7% only.