The Role of Checkpoint Inhibitors in Advanced Lung Cancer

Heather Wakelee, MD

Today, we are discussing the management of advanced lung cancer patients being treated with checkpoint inhibitor antibodies, a type of immunotherapy, with Heather Wakelee, MD, who is an associate professor of medicine at the Stanford University Medical Center in California where Dr. Wakelee specializes in the treatment of patients with lung cancer. At the recent Thoracic Cancer Symposium, that was held March 16th to March 18th in San Francisco, Dr. Wakelee discussed the management of lung cancer patients who have early or delayed progression while being treated with an immune checkpoint inhibitor.

-Interviewed by Anna Azvolinsky, PhD

OncoTherapy Network: First, what are the immunotherapies that are currently available for treatment of lung cancer and how do they work?

Dr. Wakelee: It’s really been an exciting few years for lung cancer therapy in regard to these treatments. So, we actually have three drugs that are approved as immunotherapy for lung cancer. All three are what we call immune checkpoint inhibitors. And they are all focused on the PD-1 [programmed death 1] or PD-L1 [programmed death ligand 1] pathway and that pathway is part of the immune regulation, so it’s a way that our body has of telling the immune system when something is normal versus not normal.

Obviously, if our immune system starts to attack everything that it sees then we end up with autoimmune diseases like certain types of arthritis or lupus. So, it’s important that we have that regulation so the immune cells can fight what they are supposed to, but ignore what is normal. And tumors, one of the ways they get around the immune system is to trick the immune system that the tumor is actually a normal part of us. And one of the ways that it does that is with this PD-L1 protein.

And so if a tumor has a lot of PD-L1 expression which means the protein is found on the cell surface, then if the immune cells come in to try to attack the tumor, they see that PD-L1 signal, thinks that the tumor is part of the normal tissue and then backs away. So, what these drugs do is they block the interaction between the PD-L1 that the tumor might be expressing and PD-1, which is the receptor that is on the immune cells that recognizes PD-L1.

Now, it’s all a lot more complicated than that and there are a lot more immune regulators besides PD-1 and PD-L1, but these were particularly good ones to go after with drugs. So, what happens is that when one of the drugs is in the system then the drug blocks the PD-1/PD-L1 interaction and therefore, if a tumor is trying to hide by expressing a lot of PD-L1, if one of the drugs is there, it doesn’t matter if there is PD-L1 on the tumor because the immune cells are not going to see it and therefore, the immune cells are going to have a better response to the tumor. That is the theory and it turns out that that theory is correct for about 20% of tumors. If you give a patient with lung cancer one of the drugs that blocks PD-1 or PD-L1, about 20% of those patients will have a really good response where now the immune system can recognize the cancer and attack it and get that cancer back under control for a while.

So, the three drugs that we have are nivolumab, also atezolizumab, and pembrolizumab.

OncoTherapy Network: For those patients with advanced lung cancer treated with either an anti-PD1 or anti-PD-L1 antibody, what are the range of possible outcomes as far as response or no response, and what does that depend on?

Dr. Wakelee: So, I mentioned that about 20% of patients overall are going to have benefit, but there obviously are different groups of people who are more or less likely to benefit. One of the nice things about these drugs is that it doesn’t matter if a tumor is squamous cell type or adenocarcinoma type or the other subtypes of lung cancer. That part is not as important. But what matters is that PD-L1 expression level, so how much is the tumor using to get around the immune system versus something else. Because it makes sense that if the tumor is not depending on PD-L1, then blocking that won’t matter. It is only for the tumors where that is a big part of their way to escape the immune system.

So, one of the things we can do to figure out who is more or less likely to benefit is PD-L1 expression, which is a test that can be done by a pathologist, from tumor tissue that has come out of the patient or with a biopsy. So, we know that patients who have really high levels of PD-L1 expression then maybe closer to half of patients may have benefit, meaning that the tumor is going to stop growing or potentially shrink. If there is very low expression, sometimes that is just because we are not testing for it very well so even if there is no expression, you are still going to have some patients whose tumors stop growing or shrink, but it’s more likely to happen if you find high levels of that protein.

OncoTherapy Network: For those patients who have a clear early progression while on treatment on an immune checkpoint inhibitor, what are the options?

Dr. Wakelee: That’s a great question, and it brings up the point that we have a lot of enthusiasm and hope about these drugs and obviously most people living with cancer are hoping that this will be the thing that makes a big impact for them, but it’s hard when the drugs don’t work. The truth is that they only work for a minority of patients so for more than half of the patients, these sorts of drugs don’t work at all against their tumors. So, it’s important to be able to recognize at that first scan, which we usually do around 2 months, if the tumors are really growing then unfortunately, that probably means that the drug is not working and we may have to go back to a more conventional treatment which is mostly chemotherapy, but can be quite effective for a lot of people. 

OncoTherapy Network: And for those patients who have a response that is then followed by progression months or even a year later in the course of their disease, what are the options then?

Dr. Wakelee: So, when people have had a response and lost it, it’s a bit different than when there has been no response. So, for those with no response, we really wonder whether the PD-L1 and PD-1 pathway is actually important for their tumor. But, if someone has had a response and then lost it, then we know that that checkpoint inhibitor and the PD-L1/PD-1 pathway is important for that tumor, but the tumor has figured out a way around it. So, then we are more motivated to figure out how to get that response back.

So, some of the ways to think about doing that and most of these are still in clinical trials because we don’t have a way that we know works for sure, but we can try to get the immune system working again. People are talking about doing radiation of particular [tumor] areas that are growing, whether that might stimulate an immune response again or adding in other drugs that also block other parts of the immune system pathways, other checkpoint inhibitors.

So, we don’t have one that we know necessarily works in lung cancer. In melanoma, they combine a checkpoint drug-one of the PD-L1 or PD-1 drugs-with something called a CTLA-4 [cytotoxic T-lymphocyte associated protein 4] inhibitor, and CTLA-4 is another part of the immune checkpoint that usually prevents immune cells from recognizing normal tissue, but that tumors can sometimes use to kind of evade that detection. So, blocking both you are more likely to get a response against the tumor, but there is also higher risk for autoimmune disease. So, those are the things we do to get the immune system to re-respond. Otherwise, if someone has had a response and lost it, we still have traditional treatments like chemotherapy or if it’s a patient who has a particular targetable gene mutation then we can go after those sorts of treatments, too.

OncoTherapy Network: As far as treating these patients with these checkpoint inhibitors and seeing a response, what are some of the important questions that we haven’t discussed but that clinicians such as yourself have?

Dr. Wakelee: I think that we have talked a lot about the response and the potential benefit, but I think it is important that when we talk about these drugs to think about the potential risks as well.

So, these drugs do have the potential to cause autoimmune diseases. And that can be a reaction almost anywhere in the body. People can get a rash, if it’s a skin reaction, they can develop changes in their bowels, if it’s a problem going on in the gut. Some people will end up with breathing issues if it’s a reaction in the lungs. Some people end up with low thyroid levels and have to get thyroid replacement. So, I think it’s just important for people to know that if these drugs are being used, you can’t predict side effects as well as with chemotherapy.

There is a lot of variability so it’s a matter of monitoring and being aware of the things that could happen. If something is going on and it can be found quickly, we can usually fix it pretty well with steroids, but there are a lot of unusual symptoms that can develop and people just need to be in touch with the healthcare team, and for the healthcare team to be aware and to be thinking about all of those things.

OncoTherapy Network: Thank you so much for joining us today, Dr. Wakelee.

Dr. Wakelee: Thank you.