Dr Mark Socinski on How Targeted Therapies Have Impacted Lung Cancer Outcomes

Mark A. Socinski, MD, executive director at AdventHealth Cancer Institute, discussed the emergence of targeted therapies for lung cancer and their ongoing impact on outcomes for certain patients. Socinski also discussed immune-mediated adverse events seen with immunotherapy and why they may indicate benefits for patients when mild to moderate in nature.

Transcript

Can you discuss the emergence of targeted therapies for lung cancer and their indications?

So in 2024, next year, we will be celebrating the 20-year anniversary of the discovery of EGFR mutations in non–small cell lung cancer, and this set off a chain of a number of observations looking at specific DNA alterations. In 2007, ALK fusions were described; in 2011, ROS1 fusions; shortly thereafter, BRAF; shortly thereafter met exon 14 skip mutations—and the list goes on and on. The story has been—again, getting back to the fact that one size does not fit all—is that these specific DNA abnormalities predict for greater benefit from a class that we would call targeted therapies, than the relatively nonspecific chemotherapy, and the fact that these typically tend to be groups of patients that don't realize the same benefit from immunotherapy.

So, the development of targeted therapies has been incredibly impactful on the outcomes of patients. And just in terms of looking to the future, we know that many of these targeted therapies induce a response, and that response may last 1, 2, 3, 4, even 5-plus years. And then one of the biggest challenges now is why do the tumors become resistant to the targeted therapy? Treating resistance to the original treatment is our next big challenge, and there are other targeted agents that are being developed specifically for those patients who develop certain resistance mechanisms to the first line of targeted therapies.

Your past research suggests that low-grade immune-related adverse events may be associated with improved survival in advanced NSCLC treated with immune checkpoint inhibition. Could you discuss this finding?

The use of immunotherapy is a strategy that tries to reengage the patient's immune system to fight the cancer. We know that can happen, and we also know that there are a long list of immune-related side effects. And what that suggests is that, in addition to targeting the patient's tumor, it is also targeting part of the normal patient. The common things we see are colitis; we see sometimes skin rash or dermatitis; we can see inflammation in the lungs; we commonly see thyroid alterations and these sorts of things, thinking that the immune system has become activated. And there have been small reports suggesting that if you had one of these immune-related adverse events, or side effects, if you will, that patients tended to do better. So the question came up, "Is it just simply a sign of immune system activation?"

The reports initially were relatively small, and we embarked on a large study of 3 large lung cancer trials specifically trying to look at that in lung cancer, and made the observation that those patients that had some mild to moderate side effects that were felt to be immune-related did have better survival, suggesting that the immune system is turned on, and that that resulted in a benefit manifested as patients were living longer. The interesting thing is that if you had a high-grade or serious to life-threatening immune-mediated reaction, your survival was actually shorter, whether it was because you probably had to stop the immunotherapy or the side effect was more on the catastrophic side than if it were mild to moderate. What it taught and what I've said for a long time is we actually want a little bit of immune side effects—it seems to benefit the patient. But it's important for physicians to get the message that identifying the immune-mediated adverse events or side effects are important early on so that you can implement the appropriate supportive care, keep them from becoming life-threatening or serious, thereby allowing the patient to realize the benefit of immunotherapy. So I think that's the message.

All of that study that we published in JAMA Oncology was in lung cancer. We've extended the observation to include other cancers—it was over 10,000 patients that were included in a subsequent analysis, but it includes other tumors like breast cancer and bladder cancer and other GI tumors and these sorts of things. So it's not necessarily specific to lung cancer, but it's just a larger analysis that really confirms the observation that we had in the lung cancer trials.