John Haanen, MD, PhD
Immunotherapy is more than just hype, says John Haanen, MD, PhD, head of the Division of Medical Oncology, The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital. However, for oncologists to apply it to its full potential in lung cancer, a deeper understanding of how and for whom it works is needed.
“Immunotherapy in lung cancer is here to stay, and it will be more and more important in the coming years—as a single agent, but probably have more significance in combination,” says Haanen. “Therefore, understanding the background and the mechanism of action of immunotherapy is going to be more important if you want to utilize it. It will explain why immunotherapy can or cannot work, and it will also explain what you can expect, as far as toxicities are concerned.”
In addition to safety, several other challenges regarding immunotherapy remain in lung cancer, including how the dynamic nature of PD-1/PD-L1 works, the role of PD-L1 testing, and what effective biomarkers will emerge for immunotherapy in lung cancer.
The best combination regimens and the ideal patient population for those treatments are also still largely unknown. To shed light on some of these questions, OncLive
spoke with Haanen, who focuses his research efforts on immunotherapy.
OncLive: Is there a learning curve for oncologists, in terms of handling toxicities with immunotherapies?
: Anti–PD-1 drugs appear to be quite safe; toxicities are usually not that severe, and only 10% of patients will develop grade 3 or 4 toxicities. However, it is still the early days. I suspect that the longer we are able to give this type of drug, the more toxicity we will see.
In other types of tumors, there is accumulation of side effects occurring with so-called “safe drugs,” such as anti–PD-1 agents. Once we step into combination immunotherapies—for instance, the combination of CTLA-4 blockade and PD-1 blockade—the toxicity rates will suddenly increase. Then, we are confronted with toxicities that pulmonary oncologists have never seen.
It is important to realize that, if you start combining different things, more challenges will happen. You need to have, at home, a team of doctors that can help you manage these toxicities. For instance, with combination therapy, you need an endocrinologist and a gastroenterologist, because patients might develop hypophysitis or colitis. You really need those experts to deal with that.
What role does PD-L1 testing play in lung cancer?
PD-L1 testing is a very complicated story. We’ve learned that PD-L1 expression can be very dynamic, so it depends at what point in time you look at PD-L1. We know that PD-L1 expression by tumor cells within the tumor microenvironment can be induced by an interaction between the immune system, the T cells, and the tumor. Therefore, when T cells are arriving at the tumor site, they are activated and they may recognize the tumor.
Because of that, they may induce PD-L1 expression. It is not something that is always there. There is oncogenic-driven PD-L1 expression, which is just due to an oncogenic event that occurs in the tumor. Mostly, we think that PD-L1 expression is induced by an ongoing immune response. Knowing that means that PD-L1 expression tells you something about the interaction between the immune system and the tumor, so it could be a very positive indication that an anti–PD-1/PD-L1 drug may work.
However, because it is dynamic and a complicated test, it means that we may see heterogeneous expression or expression may come up later after we have already looked. If we use tumor material from 1 year before, the expression may be completely different by the time we give the drug.
Those are things we have to realize when we think about PD-L1 expression. If you look at the outcomes of patients, you see a difference between those with low PD-L1 expression versus high PD-L1 expression. However, there is not a clear-cut threshold for the PD-L1 expression you need, in order to get a good response to an anti¬–PD-1/PD-L1 drug. Therefore, I don’t think PD-L1 expression is a very good biomarker to select on.
Without a clear biomarker, how should oncologists decide which patients should receive immunotherapeutic agents?
If you look at the targeted agents, especially in non–small cell lung cancer, you need a mutation for them to be very effective. In immunotherapy, it is much more complex. We need several things. We know that the tumors that are highly mutated respond better, so the smokers with EGFR
mutations will have a higher response rate.