Rohs Reflects on Therapeutic Approaches in Early- Vs Late-Stage Lung Cancer

With an influx of clinical trials and addition of immunotherapy in the adjuvant setting of lung cancer, Nicholas C. Rohs, MD, said how energizing it has been to have something to talk about for his patients with unresectable stage III non–small cell lung cancer (NSCLC) following chemoradiation.

“It used to be we would give our chemoradiation, cross our fingers, and hope for the best,” said Rohs, an assistant professor of medicine, hematology, and medical oncology, Icahn School of Medicine, Mount Sinai. “Now, we have another intervention that was proven to help out, and I think that it's really a nice world to live in right now.”

In an interview with OncLive, Rohs shed light on the developments and approaches to treatment in patients with early- and late-stage NSCLC and how the advent of immunotherapy, specifically with durvalumab (Imfinzi), has invigorated the field.

OncLive: What are the differences in the management of early vs late-stage lung cancer? When we look at the stage III lung cancer setting, how has the PACIFIC data impacted how you approach treatment?

Rohs: This is the perfect time for us to be talking about early-stage lung cancer management, or management of locally advanced diseases. On the heels of the amazing evolution we've had in metastatic cancer treatments, right behind that the early-stage and locally advanced diseases have had a real amazing evolution, as well.

As we all know, the PACIFIC trial was probably the one of the first triggers to this evolution. These are for patients with locally advanced NSCLC who are not amenable for surgery and proceed with chemotherapy and radiation. These patients can go through their standard chemotherapy and radiation, and then they're offered adjuvant immunotherapy with durvalumab. This trial showed that doing that [approach] absolutely helped out these patient populations.

However, it came with a couple of really important questions that we ask now. It adjusted the way that I approach these patients when I first talk to them. Chemotherapy and radiation have gotten much better over the years, particularly the radiation component—I feel that it is much more tolerable. My colleagues in radiation oncology have gotten much better about focusing down the radiation and sparing what I call the "collateral damage" to the healthier tissues.

A lot of patients get through it better, but it's still not a completely benign process. A lot of these patients still have significant comorbidities; a lot of them can get exacerbated, have heart failure, and other underlying cardiovascular pulmonary diseases that we have to be really thoughtful about. I also have to think about when I get my patients through chemotherapy and radiation, the next step is immunotherapy and I have to think about what that means for that patient at the end of chemoradiation.

I often start the conversation talking about the main problem in front of us: "We're going to go through chemotherapy and radiation. This is what it looks like, and these are the chemotherapies I'm going to talk to you about." But then at that first initial conversation, that's when I give what I call, "my warning shot." I say, "By the way, I know that we have a lot to process right now. But in the future, we're going to be talking about immunotherapy after these treatments."

At the time when [durvalumab in this setting] first came out, the dosing schedule was every 2 weeks for up to 1 year, which was a little bit of a shock to some of my patients. That's why I did start with that warning shock, because that is a long duration of therapy at a pretty good frequency. However, I sort of attenuate that and say, "These are generally well-tolerated treatments and the treatment visits are relatively short."

Now, I'm also thinking about my patients and how they get through radiation. A lot of these patients have radiation pneumonitis, or irritation of their baseline COPD, and asthma syndromes that many of my patients have. One of our biggest concerns is pneumonitis risk in this patient population; it's real and it's something that we do have to consider. As we get to that point, near the end of chemoradiation, I restart the conversation with my patients and say, "Remember, we mentioned immunotherapy before; I want to start that conversation again." I closely evaluate their breathing status.

For the majority of my patients, similar to the PACIFIC trial, I do get interval CT chest scans without contrast at the end of therapy to make sure their lung fields look relatively clean and ensure that nothing as far as their disease changes in a negative way. Now we have sort of a shared decision-making discussion at the end about whether they want to proceed. It's an exciting opportunity for our patients, so I generally encourage it. Though, I do think that there are some particular subpopulations we have to be concerned about, or at least have a different kind of conversation with. These 2 populations are low [PD-L1] expressors and patients who have actionable mutations, like EGFR and ALK.

Generally, these patients [with EGFR or ALK abnormalities] don't have as robust of a response to immunotherapy as other patients with lung cancer do. As we've seen from some of the data, it's not as convincing that those patients generate benefit from adjuvant immunotherapy in that setting. This is where I have a robust shared decision making, and I say, "Honestly, I don't know if I can help you here. If you are extremely motivated, and you understand the risks of immunotherapy, I think it's reasonable for us to proceed." But in general, I don't think that that's probably the right patient population to use adjuvant immunotherapy.

For the lower PD-L1 expressors, I have a little bit more of a relaxed conversation, because many people understand that PD-L1 is not a perfect predictor. It's what we're using right now to help understand responses or help predict responses to immunotherapy. However, it's a very variable number, but it can be very subjective per pathologists' review. I've seen a patient who has had 2 biopsies with 2 completely disparate PD-L1 numbers. It really speaks to the heterogeneity of this and we can't use that as definitive biomarker. Generally, patients with lower immune expressions did not do as well in these trials. However, I think it's reasonable.

Again, we talked about the risk of side effects. Honestly, the biggest barrier for most patients in that setting is actually the schedule. When we originally were talking about every 2 weeks for up to 1 year, that was difficult. However, we have seen a change in some of the dosing regimens for a lot of these immunotherapies.

Now, we have more flexible dosing options, and a lot of patients have the opportunity to go on a monthly dose. A lot of that is being studied in clinical trials right now. Many of the different clinical trials that are coming out for these adjuvant options are giving different dosing schedules, which is a patient centric way to approach this.

If you should have these patients who, after undergoing chemoradiation, cannot handle another treatment, what do you do for them? Can you delay the start of durvalumab?

That is an important question. There's a fair patient population that comes out of the back end of chemotherapy and radiation and is not really in the best clinical shape to start a new systemic therapy—whether it's just that they're completely worn down, they have side effects, or I have some questions about their breathing status. Do they have pneumonitis, and is it subtle? What's the right way to approach that patient? Everybody does it a little bit differently. The thing that we always keep in the back of our mind is the data from the PACIFIC trial generally lean towards patients having a better benefit if they started immunotherapy closer to their radiation completion.

Ideally, I'd love to get those patients on adjuvant immunotherapy 2 to 4 weeks after their chemoradiation. However, that doesn't mean that if they need more time, I won't still consider it. The trial allowed for longer durations [between starting durvalumab]; within an 8- to 9-week window I would consider adding the immunotherapy. Beyond that, I'm not really sure what the benefit is at that point. In advanced disease, we know that if there is some residual disease hanging out, adding an immunotherapy later still may be beneficial, though I don't think we've formally answered that question in a trial. Therefore, as with all of my patients, you look at the patient in front of you and you take all of the different variables into play: their health, their comorbidities, and their ability to get to these treatments in a reliable fashion as far as their psychosocial background.

You make a shared decision with them. Sometimes it's a patient decision, and they say, "I hear what you're saying. I just don't think I can do this right now." However, I found that most patients are motivated, and they want to try and get [to remission]. I’ll say, "Hey, I'll see you again in 2 weeks. Let's see what you look like, let's recheck and reevaluate." We just keep a close eye on those patients, just to make sure that they're recovering well, that we're making sure that they get the best care possible, and then to reevaluate them if immunotherapy is appropriate.

You mentioned that one of the patient populations that are not ideal to receive adjuvant immunotherapy are those with molecular abnormalities. Therefore, if you're wrapping up chemoradiation on a patient, and you do molecular testing and they do have an EGFR mutation, for example, are you looking to the ADAURA data to see if you can give a TKI like osimertinib (Tagrisso)? Or is there another approach that you would take?

For patients who are in the stage III setting after chemoradiation, I usually know at that point if they have an actual mutation. I'm lucky enough that in my system, we reflexively test at least all of our NSCLC cases for actionable mutations. I know that they have a mutation at the beginning of chemoradiation.

The ADAURA trial is definitely raising a lot of questions about adjuvant TKIs. It's not in a setting of post-chemoradiation; it's in the setting of post-resection, but I'm sure some people are thinking about extrapolating those data. I'm not doing it yet.

The appropriate answer is probably a clinical trial, because those are going on in these adjuvant settings. It is an area of interest. I have some concerns about it and using an adjuvant TKI may be more of a delay tactic than a cure tactic. These TKIs are what we think of as static, not cidal, meaning that they're keeping the disease at bay, and are not necessarily completely eradicating it. This can be a very meaningful end point and delays disease recurrence, generally, with good quality of life [QoL], given the tolerance of many of these pills.

However, I'm concerned about what type of disease may be recurring when they have that recurrence—if we are creating a much more complicated genetic landscape for these patients. We know that in the advanced setting, when we give TKIs like osimertinib upon progression, there's a really varied molecular resistance mechanism that we're seeing in these patients. I never know what to expect, so I want to make sure that I'm not actually making the situation tougher for my patients if they do have that relapse.

However, if we have trial data showing that we are significantly delaying disease recurrence with good QoL, and hopefully, prolonging overall survival, that will change the way that we think about this. The trials need to be completed and done in that setting. Of course, in the resected setting, the ADAURA trial is very intriguing. We have to think about the cost of these medications and the tolerance of these medications.

Are you doing molecular testing multiple times in a patient throughout their disease course?

As far as molecular testing goes in these more local diseases, I generally just do up-front molecular testing unless they have disease progression, and then I'll probably recheck their molecular profile, often through liquid biopsies so it's noninvasive—unless I have a reason to biopsy them to see if there is some evolution in this genetic component. If it's still there, or if it's different, I want to make sure I am giving them appropriately treatment.

However, that will likely evolve soon into something that we're doing at Mount Sinai Hospital. Something we're very interested in is watching the evolution of these genetic markers during the care plan, and we are developing longitudinal studies to look at genetics throughout care. I do think that that's going to be a very important part of how we manage patients, and it's still something we're learning about. However, it's really intriguing to think that we can keep a pulse on the patient's disease throughout treatment, and potentially react quicker to changes before we actually see radiographic or clinical evidence of progression.

Does your approach to molecular testing shift if the patient has early-stage vs metastatic disease?

In the general community, not everybody is testing molecular for earlier-stage disease. Given the fact that I'm fortunate enough to be in an academic Institute, we do test all of our NSCLC cases up front for molecular markers. I do think it helps us understand the disease type and how best to approach it, what treatments to offer, and also what treatments to avoid as far as immunotherapies in these patients go. Also, we are really trying to learn more about these types of diseases and how to treat them in the early-stage setting. These molecularly driven diseases do behave differently, so to gather these data and to get patients into appropriate clinical trials to learn more how to best care for them is really important.

What differences in treatment are there, if any, between the institutions and satellite locations?

As health care evolves, there is a very quickly emerging concept of large hospital systems, particularly in the New York area, and many hospital systems have bought up smaller hospital systems, so they've developed clinics into satellite sites. With Mount Sinai, we actually have many different satellite sites in Brooklyn, Queens, and Long Island. Our hope is, is that the care is not very different between those sites.

The important difference is that not every satellite site has a subspecialist. It's not always easy to have a lung cancer expert in every satellite site that you go to—we're doing our best to make that happen. I do think that the care is pretty uniform throughout our satellite sites. However, it's tough to keep up with all these data.

I am a subspecialist and I have trouble keeping up with the lung cancer field; it's evolving so quickly. Therefore, I can only imagine if I was seeing a patient with breast cancer, one with lymphoma, and one with prostate cancer in my lung cancer clinic and having to keep up with all those advances, too.

The way that we hope to address that is by encouraging all of our physicians at satellite sites to present cases at interdisciplinary tumor boards. Before the coronavirus disease 2019 pandemic, I actually had a virtual tumor board, which I've continued, and our other in-person tumor board has converted over to a virtual board. It allows much easier access for our satellite sites to participate and to get expert inputs from multidisciplinary experts; we have our radiation, surgery, medical oncology, and pathology specialties, so it's great to have those resources.

Another way that we have sort of helped out with this is a lot of our pathology testing is centralized. One of the most critical components is really subclassifying that disease: What type of disease are we dealing with? What are the molecular markers? What are the immune-based markers? Then, we can appropriately treat them, and then slowly, we are going to be expanding our clinical trials out to these types of satellite sites.

That's the next hope and dream that we can not only get uniform, excellent care at all of our sites, but then to give every patient, whether they have the ability to get into 1 of our more central locations or satellite sites, the opportunities to participate in these exciting clinical trials that we have.

What else is important to mention on how you treat these patients?

The lines are blurring a lot between early- and late-stage diseases because of how quickly these areas are evolving. There was a recent paper out in JAMA Oncology about adjuvant therapies being translated from the advanced stage, and that there's a big delay between advanced treatments getting to the adjuvant settings. We are really closing some of those gaps because of how quickly the data are coming out and how quickly these trials are able to be put together.

Because we're having such fantastic success with a lot of these new therapies in the advanced stage, we're able to see early signals of benefit in earlier-stage tumors. A lot of the stuff that I use in my advanced-stage patients are quickly trickling down to my earlier-stage patients with very encouraging signals of benefit.

We're all blown away by some of the neoadjuvant data that we've seen, particularly in immunotherapy with or without chemotherapy combinations. There is still a significant excitement about adjuvant TKIs and other therapies going on in this setting. I have a feeling that really early- and late-stage settings, while there are very big differences in how we think about the patients and how we approach them, a lot of the therapies will be similar.

Editor's Note: This interview was conducted prior to the December 2020 FDA approval of osimertinib for use as an adjuvant treatment following tumor resection in patients with NSCLC whose tumors harbor EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.