Navigating Nuances in Early and Metastatic Lung Cancer Treatment

The treatment paradigms of early-stage and metastatic lung cancer have expanded significantly in recent years with the addition of immunotherapy and targeted therapy options, said Brendon Stiles, MD, who added that challenges regarding screening, molecular testing, and localized therapy remain areas of ongoing research.

“I tend to be an optimist,” Stiles said. “A little bit of that is needed in lung cancer because it used to be somewhat hollow, but there is now increasing hope. Lung cancer has become so complex that it is hard for the layperson to follow; there are 7 frontline treatments for different types of adenocarcinoma, even aside from immunotherapy.”

In an interview with OncLive^®, Stiles, a thoracic surgeon at NewYork-Presbyterian Hospital and an associate professor of cardiothoracic surgery at Weill Cornell Medicine, discussed his approach to treating patients with early-stage and metastatic lung cancer, the importance of molecular testing and screening, and remaining challenges in the space.

OncLive^®: How do you first approach your patients with early-stage lung cancer?

Stiles: Patients with early-stage disease are more often curable [than those with metastatic disease]. Nevertheless, these patients need to be staged carefully to make sure that they have early-stage disease. That is often done with CT or PET scans. Often, [patients may be staged] by invasive staging, which can be done bronchoscopically or with a mediastinoscopy. 

I try to think of each patient as an individual. I try to assess the tumor characteristics of that individual and then tailor treatment appropriately. [This is similar to] what we do in the stage IV setting because we really believe in individualized therapy.

What factors do you consider when determining up-front treatment selection?

We know so much about tumors now that we can characterize them radiographically by size, PET uptake, tumor consolidation ratio, and how much of the tumor is ground glass–part solid versus solid. Those [characteristics] factor into my decision when I talk to patients about their risk of lymph node metastasis. [Also, this informs] the potential for sublobar resection. If we are considering a wedge or a segmentectomy, we’re still going to do a good lymph node analysis, but more frequently, we find that we can take out less lung. We think that has some long-term benefits for patients.

That said, we have to be careful about when we apply that because it is still a bit ahead of the randomized control trials, particularly for medically operable patients with good [functional status]. I try to think about each of those [factors] carefully and tailor the operation to the individual patient. 

Do you recommend getting up-front molecular testing for all patients with early-stage disease?

I am really fortunate to be at a place where we are able to do molecular testing on all of our early-stage patients. That has been eye opening for me because unless we test routinely, we don’t know what the lay of the land is going to be in terms of mutations. Over 30% of our patients have EGFR mutations. Also, it is probably not always the ones we would expect: the female never-smokers. It is often smokers, older patients, and even males [who harbor EGFR mutations]. Therefore, we have learned a lot by routine testing.

We can also identify other targetable mutations that, although not yet applied to the early-stage setting, may one day be applicable to that space. 

What roles do localized therapies, such as surgery and radiation, play in early-stage lung cancer treatment compared with targeted therapy and immunotherapy?

Surgery is still the mainstay of treatment for early-stage disease. That said, increasingly, we live in a world where we should be considering multimodality therapy. That is particularly true of stage II and stage III patients; it is routine to give those patients chemotherapy in the adjuvant or neoadjuvant settings. Chemotherapy really is the standard [in those spaces]. 

Increasingly, we are seeing trials of neoadjuvant or adjuvant immunotherapy. We just saw an FDA approval for EGFR-targeted therapy in the adjuvant space. There are lots of exciting things going on, and it is more important to understand the molecular lay of the land for early-stage patients than ever. Obviously, there has been an explosion of interest in immunotherapy, including PD-L1 staining to understand which patients may be eligible [for that approach].

There is also a place for radiation therapy, whether that is through an induction platform with chemoradiation or adjuvant radiation therapy for patients with resected disease. [Radiation therapy] may be a bit on the downswing now because of some recent trials, but there is a role for it as well. Even for some really early-stage patients, stereotactic radiation may have a role. Sometimes, particularly for patients with limited pulmonary function, we may consider [stereotactic radiation] as an option for local treatment. 

Shifting gears to the metastatic setting, what are the most notable changes in treatment approaches? 

Everybody knows that the metastatic setting is really amazing because there are so many treatment options. Understanding the molecular subtype of cancer is critical [in the metastatic space]. We have targets like EGFR, ALK, ROS, BRAF, NTRK, MET, and RET. There are just so many options and many are [targeting] rare [alterations]. Again, it gets to that principle of having to look for [mutations] to know if they are there. That is all on the targeted therapy side.

Obviously, the other side is for patients who are eligible for immunotherapy, which is a whole different paradigm based on PD-L1 expression and combination therapy. 

I see a lot of late-stage patients as part of the initial diagnosis phase or sometimes performing a procedure to diagnose metastatic disease. We have gone from a time when there wasn’t much hope to a time of figuring out what type of cancer a patient has and treating it appropriately. I would love to see everything move into the early-stage setting—and they are slowly making their way there—but it’s so critical to know the histologic and molecular subtype of a patient with stage IV disease.

Do surgery and radiation factor into the metastatic treatment landscape?

That is another very exciting area because traditionally, no. We wouldn’t think about surgery or radiation therapy in the stage IV setting. [However,] there is an evolving concept of oligometastatic disease in patients with limited metastatic disease where perhaps there is a role for local therapy.

I don’t want this to [evolve] into a place where we are doing local therapy on all patients [with metastatic disease] and potentially delaying their systemic therapy, because that is the most important treatment for these patients. Certainly, there are some patients who have a handful of localized metastases or primary tumors. In those cases, getting the part of the tumor that might have developed acquired resistance to treatment and be an immune-privileged space could add something to the overall picture and increase the efficacy of some of these great drugs that we have.

When do you recommend patients for clinical trials amid all of these available therapies? 

We should always be thinking about clinical trials and push ourselves to consider what else we could do for our patients. Who may be better with the therapies that we already have? How can we improve upon them? Those are good things to think about, but I wouldn’t do it at the expense of standard-of-care treatment. That is a critical consideration for all of us in the lung cancer space, but we need more participation in clinical trials.

In lung cancer, there has been a long-standing stigma and concern [regarding clinical trials]; patients don’t want to talk about it and there is likely less enrollment in clinical trials of patients with lung cancer compared with a lot of other cancers. We’re doing much better, and we’ve turned around a lot of that idea. We need more trials because we have all of these great drugs coming down the pipeline. Figuring out [enrollment into clinical trials] is an important piece of the puzzle. 

What challenges remain that research efforts should aim to address?

There are a ton of challenges. We’ve got all these great drugs, but still, some patients don’t respond, and many develop resistance. To me, one of the biggest things that we have to understand is how we can, scientifically, overcome treatment resistance to targeted therapy or immunotherapy. 

Another challenge, that is perhaps even lower-hanging fruit, is getting these great therapies that we have to all of our patients and overcoming care disparities. Those disparities have been highlighted by COVID-19 [coronavirus disease 2019] and by some of the current things going on. We know that, in lung cancer, minority patients are screened less, and there is less molecular testing. We don’t always treat to the test, but if we could overcome that and diagnose and treat all patients appropriately, we could make up a lot of ground pretty quickly.

Could you speak to the importance of screening for lung cancer?

Lung cancer screening had the misfortune of growing up in an age when there was increased skepticism about cancer screening in general. That is certainly understandable; we don’t want to overtreat or harm patients who may not have cancers.

However, lung cancer screening also has some of the best data out there in terms of decreasing mortality from lung cancer. We know that a simple CT scan can do that. We have great randomized trials that show unfortunately, still less than 10% of eligible patients are screened. That number is even less in minority populations with other socioeconomic disparities. We could really move the needle a lot by increasing our screening programs. We should be having discussions of screening with our patients to tell them about the risks and benefits [of screening] to give them the option to decide whether they want to be screened for lung cancer. 

COVID-19 has led to a decrease in lung cancer screening. Could you elaborate on the significance of this and how the field could combat this?

Screening is down, but we also know that diagnoses are down, perhaps by as much as 50% in some parts of the country during certain months. Ordinarily, that would be something we would love to talk about—a decrease in lung cancer—but we know that those cases haven’t gone away. Cases are going undiagnosed during COVID-19 because patients are staying away from doctors. That is going to cause a bit of a lag [in diagnosing]. I worry that a lot of the gains made in lung cancer may be erased. It’s never been more important to be in close communication with [your patients] to understand when they should be screened and [convey] a safe way to do it within the COVID-19 environment. Certainly, if patients have symptoms, they shouldn’t push them off for fear of COVID-19. We need to be careful, but we need to make sure that we diagnose lung cancers at a time when we can still treat them.

What is your advice to community oncologists who do not exclusively see patients with lung cancer?

A lot of community oncologists out there are working incredibly hard and they are seeing all different types of tumors. They may only see a handful of [lung] tumors each year, so they might not know the nuances of [treatment]. They may never see a patient with one of these mutations that we now have first-line drugs for. Education, getting the word out, and gaining some expert advice is always helpful when needed. At least talking to a specialist is good and perhaps some of the barriers have decreased with telemedicine.

What exciting developments are in the lung cancer pipeline?

A lot of great stuff is happening that it is hard to keep up with. Obviously, there is excitement about KRAS inhibitors. We’ve talked about that pathway as being potentially undruggable.

There is also a lot of drugs that are potentially being combined with immunotherapies that we already use to try to increase responses and make a cold tumor hot. 

There are also some great drugs in the inflammatory space such as IL-1 [interleukin-1] beta inhibitors that we can maybe use to prevent the progression of cancer. Can we use them in combination with immunotherapy for other responses? There is so much going on; we have to continue to fund research, look to new research, and think about how we can get that research to the clinic.