Future Horizons in Lung Cancer

Immunotherapy and treatment advances in small cell lung cancer

Prof Dean Fennell - University of Leicester, Leicester, UK

I was invited to speak about small cell lung cancer and immunotherapy in small cell lung cancer. I started by talking about this is a relatively rare disease for which there have been very little in the way of treatment advances over the last decade and that the revolution that we’ve been seeing with immunotherapy, particularly in non-small cell lung cancer where we’ve seen new market authorisations for extremely effective therapy, are beginning to show tantalising signs of activity in small cell lung cancer. If you think this is a disease that has a survival associated with it of about 2-5% over two years it’s really a dismal prognosis for patients. Some of the recent data that was presented globally earlier this year around CheckMate-032, for example, which was the combination study looking at nivolumab, a PD1 inhibitor, with a CTLA4 inhibitor, ipilimumab, and this showed some very tantalising evidence of activity relating in part to survival improvement, at least signs of that, with what would be described as a multiplication of survival at the 24 month point.

So that was really a highlight of the data that I was presenting but also trying to explore questions of why small cell lung cancer might be a target disease for treatment. The fact that it’s a highly mutated cancer makes this one that might have a lot of what we call neo-epitopes which might be attractive for immunotherapeutics and also the fact that they express in part the markers which are used to now select some of these drugs. So, for example the PD1 inhibitors, we now know that the expression of a ligand called PDL1 is important in stratifying or identifying patients who are likely to benefit and certainly that’s expressed within patient tumours with small cell lung cancer although at a lower level in those disseminated small cell cancers compared to limited ones.

So collectively the rationale is there for treatment, the signals are there, and I talked a little bit also then at the end about some new treatments which are being evaluated, so new trials, pivotal studies, and also possible new strategies for combining immunotherapies in order to improve outcomes.

Can you give us some examples?

In terms of the trials actually, there are at least two major pivotal studies which are ongoing at the present time. These studies are going to be looking at combination, at maintenance therapy using combinations of immunotherapy and there are also studies out there looking at combined monotherapy of PD1 inhibition versus chemotherapy. So these are studies which will be rolling out over the next year or so.

In terms of novel studies actually the field is exploding really in terms of how many combinations are being examined, in particular looking at PD1 novel combination studies. We have particular interest here in the UK at the moment at looking at a class of drug known as a focal adhesion kinase inhibitor which has been shown to kill tumours essentially, or shrink tumours, through a mechanism that was hitherto unsuspected, actually, but identified as an immune mediated tumour aggression mechanism that’s blocked essentially by the PDL1/PD1 checkpoint. So by combining a PD1 inhibitor with a FAK inhibitor there’s a very strong rationale for doing this in order to see synergy and this is something we’re evaluating and the opportunity may be there in the future to look at small cell lung cancer.

That was one example, the other one was the possibility of combining drugs that can switch off the suppression of many epitopes which is normally something which may happen through the so-called epigenome, the genomic marks, histone marks, which can be used to switch off specific genes. By switching off genes where there’s a particular mutation that might otherwise be expressed and drive an immune response, it has been shown now that by switching off the epigenetic, the gene suppressing mechanism, that there is synergy, there is enhancement of immune checkpoint inhibition in vivo. So it’s likely that in the future we’ll see some novel combinations demonstrating activity around that concept and I believe those trials are just starting now so that’s something for the future possibly for small cell lung cancer patients.