PracticeUpdate: Haematology & Oncology

LUNG 28

Predictors of immunotherapy response in lung cancer: biomarkers, mutational load and tumour biology Roy S. Herbst MD, PhD, Ensign Professor of Dr Haffizulla: We know that immunotherapy agents have truly come of age in lung cancer. What is your opinion about the advances in biomarker studies?

Medicine and Chief of Medical Oncology at the Yale Cancer Center and Smilow Cancer Hospital in New Haven,

Dr Herbst: Immunotherapy clearly has become a new modality for treating lung cancer, just like chemotherapy, radiation therapy, and tar- geted therapy. The question now is how can we benefit more patients. We know that 1 out of 4, 1 out of 5 patients has a truly remarka- ble outcome, but the remainder don’t, so we need to develop newer and better biomark- ers. We’re doing that. There’s PD-L1, which gives an okay, not great biomarker. Some studies, including one that I led with pembrolizumab, do clearly show that higher levels of PD-L1 do predict a better outcome, so I think that PD-L1 will be used in some settings. But what is also known is some patients who don’t have any PD-L1 on their tumour, still do have benefit, so it’s not the whole story. Now what’s being done is immu- no-sequencing, meaning people are looking at tumours, sequencing those tumours, either looking at either the number of mutations, or the quality of the mutations, meaning is there a specific mutation. I think those signa- tures might be important, and then remember there’s another part of the whole component. It’s not enough to have a tumour that’s driv- ing the process. You have to have the immune system at the tumour. So, is the tumour becoming inflamed and are the immune cells coming to the tumour? I think both are being looked at right now. Dr Haffizulla: The PD-L1 status itself, would you consider that a dynamic biomarker? And you mentioned the tumour infiltrating lym- phocytes themselves, and how they stain, and how quickly you’re able to get that particular specimen stained in the right fashion, and how old that particular specimen is. Dr Herbst: You bring up some good points. It’s the interferon that stimulates the whole process. It’s a real time marker, so archival biopsies have their limits, so we’re going to need to really cast a wide net here. Look at signatures in the tumour, look at signatures in lymphocytes, look at blood-based markers,

Connecticut, speaks with Dr Farzanna Haffizulla on immunotherapy for lung cancer and advances in biomarker studies.

and all that’s being done, and we’re seeing that in the literature now, and it’s a very big area of research. We’re doing that in our own group at Yale on a daily basis. Dr Haffizulla: Still on the immunology thread here. What is your opinion of some of the immunologic biomarkers and immune neoan- tigen signatures, and looking at the mutational load of the tumour itself? How does that play in, and I know that we want to get as detailed as possible, but I know that there is also a progression of change that happens with the tumour as it’s being treated. So, how does that all play in? Dr Herbst: Well, you know, mutational load certainly plays a role. Actually, if you look, it’s really smoking. It’s patients who smoke that tend to have a better outcome proba- bly because they have more mutations. So, I think mutational load can be a guide. I don’t think it’s the whole story. We are going to have to look at exactly what mutations are there. Are there specific neoantigens? One way we’re trying to figure this out at Yale is we have a re-biopsy protocol as part of lung SPORE grant, where we have patients who get a biopsy before they’re treated, and then they’re treated with an immune therapy. Then, if they become resistant, we get a sec- ond biopsy. The reason why that’s important is then we can compare the genetic profile before and after in the same patient. So, you remove some of the noise that you see when you check between patients, and try and iden- tify what’s gained, what’s lost from the tumour when it becomes resistant. These types of studies are happening at many places now. There’s so much we know, but there’s even more we don’t know and I think this is an

Go to practiceupdate.com to watch the full video

interview with Roy S. Herbst.

PRACTICEUPDATE HAEMATOLOGY & ONCOLOGY