Heather Wakelee on the Role of Checkpoint Inhibitors in Advanced Lung Cancer

Oncology (Williston Park). 31(6):440, 442.

Heather Wakelee, MD

1.What are the immunotherapies that are currently available for the 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 immunotherapy treatments. We actually have three drugs that are approved as immunotherapy for lung cancer: nivolumab, atezolizumab, and pembrolizumab. All three are immune checkpoint inhibitors and they are all focused on the programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway, which is part of the body’s immune regulation.

The immune checkpoint pathways are critical because if our immune system starts to attack, then we end up with autoimmune diseases like certain types of arthritis or lupus. It’s important that we have that regulation so the immune cells can fight what they are supposed to, but ignore what is normal. As for tumors, one of the ways they “get around” the immune system is to trick the immune system into thinking that the tumor is actually a normal part of us; one of the ways that it does that is with the PD-L1 protein.

If a tumor has a high level of PD-L1 expression and immune cells try to attack the tumor, they see the PD-L1 signal, think that the tumor is part of the normal tissue, and back away. The currently approved checkpoint inhibitors block the interaction between PD-L1, which the tumor might be expressing, and PD-1, which is the receptor on the immune cells that recognizes PD-L1.

Of course, it’s far more complicated than this, and there are a lot more immune regulators besides PD-1 and PD-L1, but these were particularly good targets to go after with drugs. What happens is that when one of the PD-1/PD-L1 checkpoint inhibitors is in the system, then the drug blocks the PD-1/PD-L1 interaction; therefore, if a tumor is trying to hide by expressing high levels of PD-L1, if one of these drugs is present, it doesn’t matter if there is PD-L1 on the tumor because the immune cells are not going to see it and are going to do a better job of attacking the tumor. That is the theory, and it turns out that theory is correct for about 20% of tumors. If you give patients 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, in which the immune system can recognize the cancer and attack and control it.

2.For patients with advanced lung cancer treated with either an anti–PD-1 or anti–PD-L1 antibody, what are the range of possible outcomes as far as response or no response is concerned, and what does that depend on?

DR. WAKELEE: I mentioned that about 20% of patients overall are going to benefit, but there obviously are different groups of patients who are more or less likely to benefit. One of the good things about these drugs is that it doesn’t matter if a tumor is squamous cell type, adenocarcinoma type, or any of the other subtypes of lung cancer. That part is not as important. What matters is the PD-L1 expression level, because if the tumor is not depending on PD-L1 to help it escape the immune system, then blocking it won’t matter.

One of the things we can do to figure out who is more or less likely to benefit is to measure the PD-L1 expression, which can be done by a pathologist, from tumor tissue that has been removed from the patient during a biopsy or surgery. We know that patients who have really high levels of PD-L1 expression on the tumor may have benefit, meaning that the tumor is going to stop growing or potentially shrink. Even if there is no expression, there are still some patients whose tumors stop growing or shrink with the immune checkpoint drugs, but it’s more likely to happen if you find high levels of PD-L1 on the tumor tissue.

3.What are the options for patients who have a clear early progression while on treatment with an immune checkpoint inhibitor?

DR. WAKELEE: That’s a great question, and we have a lot of enthusiasm and hope for these drugs; obviously, most people living with cancer are hoping that this will have a big impact, so it’s hard on them 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. It’s important to be able to recognize at that first scan, which we usually do at around 2 months, that if the tumors are really growing, it probably means that the drug is not working and we may have to go back to a more conventional treatment such as chemotherapy, which can be quite effective for a lot of patients.

4.For 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: When people have had a response and lose it, it’s a bit different than when there has been no response. For those with no response, we really wonder whether the PD-1/PD-L1 pathway is actually important for their tumor. But, if someone has had a response and then loses it, then we know that the PD-1/PD-L1 pathway is important for their tumor, but the tumor has figured out a way around it. In those cases, we are more optimistic that there will be a way to get the response back.

We are still in clinical trials to figure out how to get the response back, since we don’t have a way that we know works for sure. There has been talk about doing radiation for particular areas of the tumor that are growing, thinking that might stimulate an immune response again, or adding in other drugs-such as chemotherapy or targeted therapy-or other checkpoint inhibitors that block other parts of the immune system pathway.

We don’t have one combination yet that we know necessarily works in lung cancer in the setting of progression of disease on a single checkpoint inhibitor. In melanoma, they combine a checkpoint inhibitor-one of the PD-L1 or PD-1 drugs-with a cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitor. The CTLA-4 protein is another part of the immune system that also prevents immune cells from attacking normal tissue, and which tumors sometimes use to evade the immune cells’ detection. By blocking both you are more likely to get a response against the tumor, but there is also a higher risk for autoimmune disease. As for patients who have 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 try a targeted therapy.

5.As far as treating patients with checkpoint inhibitors and seeing a response, what are some of the important questions that we haven’t discussed but that clinicians may still have?

DR. WAKELEE: I think that we have talked a lot about the response and the potential benefit, but I think it is also important to think about the potential risks of these drugs as well.

These drugs do have the potential to cause autoimmune diseases, which can be a reaction almost anywhere in the body. People can get a rash if it’s a skin reaction, or they can develop changes in their bowels if it’s a problem in the gut. Some people will end up with breathing issues if it’s a reaction in the lungs. Other people end up with low thyroid levels and have to get thyroid replacement. I think it’s important for patients and clinicians to know that if these drugs are being used, you can’t predict side effects as well as you can 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 is found quickly, we can usually correct it pretty well with steroids. However, there are a lot of unusual symptoms that can develop. Patients need to be in touch with the healthcare team, and the healthcare team needs to be mindful of potential side effects, so that everyone is working together to help the patient quickly if any problems do arise.

Financial Disclosure:Dr. Wakelee is a consultant/advisor for ACEA Biosciences, Clovis Oncology, Genentech/Roche, Helsinn, Novartis, Peregrine, and Pfizer; and has received research funding from AstraZeneca/MedImmune, Bristol-Myers Squibb, Celgene, Exelixis, Genentech/Roche, Gilead, Novartis, Pfizer, Pharmacyclics, and Xcovery.