Combatting Toxicities and Leveraging Novel Therapies in Lung Cancer Care

During a visit to Columbia University Irving Cancer Research Center, CancerNetwork^® sat down with Brian Henick, MD, to learn about key initiatives in the research and treatment of lung cancer and other malignancies of the aerodigestive tract. Amid growing use of immune checkpoint inhibitors, antibody drug conjugates, bispecific antibodies, and other novel therapeutics in the field, Henick highlighted a need to better understand and predict which patient populations are most likely to develop adverse effects during their treatment course.

Henick also described his work focused on reducing reliance on prophylactic steroids to mitigate immune-related adverse effects, noting how they may cause other issues related to patient blood pressure, the ability to focus, and weight distribution, among others. He also touched upon targeted therapy approaches that may hold promise in other patient populations he treats, including those with esophageal or head and neck cancers.

Henick is a medical oncologist specializing in the care of patients with malignancies of the aerodigestive tract and the director of the Phase I Unit and of Translational Research in Aerodigestive Cancers in Medical Oncology at Columbia University Herbert Irving Comprehensive Cancer Center.

CancerNetwork: What are some clinical research efforts of yours that may improve the efficacy of emerging cancer therapies for patients with lung cancer and other aerodigestive malignancies while potentially minimizing adverse effects?

Henick: Speaking to our overall research program here, in general, the way that we tend to think about drug development and oncology, especially in phase 1 [trials], is trying to find drugs that are first and foremost going to help shrink cancer and help patients live longer. The challenge is that because we don't know what's going to be successful to achieve that, [adverse] effects end up being a secondary outcome.

One example of this was with immune checkpoint inhibitors, which have been in development for over a decade. We saw some incredible results with respect to controlling cancer and helping patients live longer. Only later did we start to realize that some patients can develop life-threatening or permanently morbid [adverse] effects. As we look back as a field at patients who experience that, it's still challenging for us to know upfront who's likely to have these [adverse] effects or not.

At Columbia, our phase 1 unit is testing new drugs, new classes of therapies, and lots of targeted treatments—antibody drug conjugates and bispecific antibodies—across a range of classes. Most of those efforts are appropriately geared towards the efficacy questions; how do we get good cancer control? However, another area that we began to look into is with respect to [adverse] effects, and this relates to some of the approved classes of therapies, like checkpoint inhibitors.

This began with pilot projects where we had been collecting blood from patients who had been treated with checkpoint inhibitors according to standard of care. We had a collaboration with our Department of Rheumatology, [including] Adam Mor, MD, PhD. In collecting those blood samples, we then looked back to see which patients went on to develop severe [adverse] effects vs those who didn't and compared what happened in the blood from one group to the other. The analysis that we [conducted] involved single-cell RNA sequencing. The nice thing about using that kind of technique is that you can get an idea of what are different kinds of T cells that are different in one group vs another. You can also get an idea of what the function of these T cells are and what processes are going on with respect to how the immune system is reacting to the tumor vs to the body.

Can you elaborate on how these T cells may be associated with adverse effects?

What we found was that different [adverse] effects seemed to have their own subsets of T cells associated with them. This was a relatively small study. It was done in about 2 dozen patients, but the concept of it was provocative. What this did was nominate certain subsets of T cells that might be involved. One subset of T cells that we saw was involved are called Th17 cells; these are driven by the cytokine interleukin-17. Interestingly, there is a drug that's approved for treatment of psoriatic arthritis that targets this cytokine. What we've done in the last year or so is launch a clinical trial testing that drug in patients who have arthritis that began in the context of treatment with checkpoint inhibitors to see if that can safely be given to patients and to see what impact it has on their arthritis. The paradigm for that trial is a bit different than what we're used to for typical trials in cancer. Usually, we're looking for patients where the cancer is not under good control, and we need a new drug to treat the cancer. The patients we're focused on for this study are patients where the cancer is already under good control, which can happen for some of these patients who have these long-lasting, morbid [adverse] effects with checkpoint inhibitors.

The main entry criteria are that they have arthritis that steroids have not been sufficient to keep under good control. This is not the only trial like that out there. There's an emerging sense across the field that this is something that's important. There's a community called ASPIRE. That has come together to try to look at this, which entails investigators at academic centers across the country. We convene at different meetings and have Zoom [meetings] every so often to review new data and to take stock of what clinical trials are looking at this.

There are other trials that are ongoing for cardiac [adverse] effects of these treatments, [including] pneumonitis and others. Hopefully, this will be an area of increasing focus. Then, the next challenge will be to apply what we learned in trials like that to the upfront development of the next generation of therapies. As we think about therapies that are showing promise in terms of efficacy in lung cancer, head and neck cancer, and esophageal cancer, can we start to incorporate what we know about toxicity earlier on in the drug development process so that we can do a better job of balancing the 2?

How can clinicians reduce or avoid dependance on steroids among patients who experience adverse effects associated with immunotherapy?

Steroids are a blunt force tool that we have to reduce inflammation that can be happening in the body, and they're phenomenally useful. We use steroids before treatment with chemotherapy often, and steroids are our first line of defense when a patient has what looks to be an immune-mediated reaction to a therapy that's being given either in the moment—an anaphylactic reaction—or some of these more classic immune-related syndromes. The challenge is that we end up bucketing [adverse] effects based on what organ they're affecting. [For example], the patient develops a problem with their kidneys after checkpoint inhibitors. All possible mechanisms of kidney injury end up getting lumped together, and you just have the common denominator of wanting to decrease inflammation by start steroids.

However, if you understand what flavors of T cells are involved in the process, or what aspects of the immune system are causing the damage, that might give us the opportunity to more specifically target the [adverse] effects. But at the moment, we're reactive. We're not able to predict which patients are likely to develop what [adverse] effects upfront. We're waiting for the [adverse] effect to happen and then intervene. The first layer of defense for intervention is not targeted. The more we come to understand why patients are having the [adverse] effects that they're having and predicting what patients are at risk for these [adverse] effects, the better. We'll be able to give more precise therapy that doesn't have such a range of [adverse] effects, like we see with steroids.

Steroids can cause many kinds of [adverse] effects for patients who are on them for a long time, [like] issues with their blood pressure, issues with their ability to focus, or their ability to sleep. It can cause issues with reflux and their weight and fat distribution. [There are] many consequences from being on steroids for a long time. That's part of the impetus for us to understand these syndromes better and to see what we can do to spare patients from treatment with those unless we absolutely have to. Then, the flip side is that it's often the case that once there's a [adverse] effect that requires steroids, patients are stuck on them because it's hard to get them off; they become dependent. For all these reasons, it's important for us to understand the [adverse] effects a bit better.

Looking ahead, where does the field as a whole need to go to further improve outcomes among patients with lung cancer and other aerodigestive malignancies?

We’re lucky in that we may have the beginnings of a blueprint already in place, at least in terms of nonsquamous lung cancer or adenocarcinoma. What we have there is basically a pie of cancers that gets divided by alterations in the genes that drive the cancers. Each driver genetic alteration has its own classes of therapies that seem to be beneficial. It causes many of us in the field to feel like these are separate diseases. In some cases, you have a patient where they have a cancer that grew in their lung; you look under the microscope, and it looks like adenocarcinoma. We know that when that problem arises because of a mutation in the EGFR gene, that’s going to point us in the direction of targeted therapies. On the other hand, if we see a mutation in the TP53 gene and we don’t see anything else, we’re not able to target it in the same way.

One of the great quests in the field in the last number of decades has been to try to find all the different driver events that can happen in lung cancer and to try to find therapies associated with them. There’s a range of success we see for EGFR, ALK, and for certain other [mutations]. [There are] wonderful therapies that work very well for years for patients to be able to achieve almost a normal quality of life. On the other hand, there are examples where we’ve not made as much progress. What it comes down to is trying to improve our understanding of the biology, of what’s happening to the cancer in each of those situations.

One concept that’s exciting to us here at Columbia is the idea of a protein that might be unique to squamous cancers, [which] can be targeted with a new therapy. We have a study that’s due to open soon with a company called EvolveImmune, and they have therapy that is designed to target a set of proteins called ULBP-2/5/6 and bring T cells to that protein. That therapy is structured in such a way that one arm goes after this protein that’s elevated in squamous cancers, and the other arm is designed to draw in T cells. We’re hoping to have open that study here in the next couple of months, and that would be a very interesting proof of concept for a therapy that might work across a range of solid tumors.

Similarly, we see promising effects in emerging classes of therapies like antibody drug conjugates. There are some that have shown promise in squamous cell carcinomas. There are other bispecific antibodies, for example, targeting EGFR, which can be amplified in squamous cancers that seem to be showing promise and may be moving towards approvals in the coming months or years.

What ongoing research initiatives hold promise for improving the prognosis of patients with esophageal or head and neck cancers?

Along the lines of what I was describing, there are different histologies that we can see in the lung and in the esophagus between adenocarcinoma and squamous cell carcinoma. Much of what I was speaking about earlier has to do with squamous cell carcinomas, which can have shared features across esophagus, lung, head and neck, and sometimes other anatomic sites as well. In particular, classes of therapies that are of interest are bispecific antibodies, particularly those that are targeting EGFR. [Additionally], antibody drug conjugates are targeting proteins that might be upregulated in the tumor, and T-cell–engaging therapies target proteins that are unique to these tumors.

For esophageal adenocarcinomas, the paradigm is much more similar to gastric adenocarcinoma. There, we're seeing more of a model that we see for lung adenocarcinoma, where there are different driver mutations or expression of proteins like HER2 that can point us towards therapies that have a higher chance of working. There are also antibody drug conjugates targeting proteins like Claudin 18.2. The simple answer is it depends on the kind of tumor to point us in the direction of what therapies are most likely to be beneficial. But across the range of [diseases], some of these new classes seem to be showing promise for our last 2 questions.