Efficacy and Safety of Checkpoint Inhibitors in Lung Cancer

Transcript:Heather Wakelee, MD: In the fall of 2016, we heard the results from the KEYNOTE-024 trial, which was a randomized study looking at the immunotherapy drug/PD-1 inhibitor pembrolizumab versus standard platinum doublet chemotherapy. The trial screened nearly 2000 patients to find the 300 patients who went on it, and in the screening, what they were looking for was really to see patients’ tissues and how many patients had enough PD-L1 expression in their tumor. The level of expression that was required to go on the trial turned out to be 50%. So, it’s a pretty high bar, but when you look at all-comers who were looked at for the trial, about 30% of patients end up having that level of PD-L1 expression—when you look at newly diagnosed lung cancer patients.

They did exclude those who had EGFR and ALK mutations, so that was a small number who were taken out. Also excluded were patients who had untreated brain metastases. That’s not a huge number, but it’s something we need to keep in mind when we’re looking at how to bring those data into treating our patients in general. But, it was a really exciting trial result. In that group of patients who did enroll in the study, the group who received pembrolizumab had a response rate of 45%, which is high—higher than what we usually see with chemotherapy. The chemotherapy response rate was close to 30%, around what we would expect.

When you look at time-to-progression or progression-free survival, those were also in favor of the pembrolizumab, and that hazard ratio was 0.5, so it was quite significant. Then, when you looked at the overall survival, there was also a statistically significant survival benefit with pembrolizumab. And the patients who received chemotherapy were eligible to switch over to pembrolizumab at the time of progression, so it became a study showing that starting off first-line with pembrolizumab actually improved outcome survival, even compared to starting with chemotherapy and switching to pembrolizumab later. But we have to keep in mind that it was a subset of patients who had that high expression. They had to have at least 50% PD-L1 expression by a particular assay, which is a 22C3 test.

Contraindications to immunotherapy are rare, but they exist. When patients come in to see me now, almost all of them have heard about immunotherapy. Most of them want immunotherapy, and many of them don’t want chemotherapy. So, I joke that I spend a lot of my time convincing people when they do need chemotherapy and convincing them when they don’t need immunotherapy—but never the other way around.

The challenge of immunotherapy is that what it’s doing is triggering the immune system to recognize the tumor in a way that’s more significant than what it was doing on its own. But when you’re tricking the immune system into being more reactive against a tumor, you can also trick it into being more reactive against normal tissue. So, that’s really the challenge: developing autoimmune disease. And the autoimmune diseases that we see can impact almost anything. People can have colitis, a terrible rash, endocrine disorders, but also cognitive dysfunction. It can get in and cause CNS problems—cardiac dysfunction. So, it’s a whole host of things, and some of them can be fatal. It’s not a class of drugs without side effects.

And, of course, patients who have underlying autoimmune diseases are at the highest risk for those problems developing. That’s really the major contraindication. People are starting to push the boundaries now. When the trials were first developed, patients with any autoimmune disease were excluded. Now that we’re seeing the efficacy of these drugs, people are pushing into “Well, what about if it’s just type 1 diabetes?” They don’t have functions of the pancreas anymore, and so now we say, “That’s probably OK.”

What if it’s just a cutaneous issue and cosmetic? Well, maybe that’s going to be OK, but what if it’s terrible rheumatoid arthritis that’s crippling? Well, maybe not. What if it’s a terrible GI autoimmune disease? Maybe not. And yet, we get pushed in that direction. So, we’re still trying to work out what the boundaries are for exclusion for people who have autoimmune diseases. Other than those autoimmune diseases, there really aren’t a lot of contraindications. There are some that are relative. There were concerns about brain metastases early on. But now, it seems that the drugs are actually pretty safe even in that setting.

Transcript Edited for Clarity