Capitalizing on Multimodality Therapy in NSCLC

Balazs Halmos, MD

Treatment recommendations in early-stage non–small cell lung cancer (NSCLC) are given with curative intent, whereas those in late-stage NSCLC are made more with disease control in mind. However, the paradigms that were once predominantly defined by surgery and chemotherapy are now being amended to include immunotherapy and targeted therapy, necessitating discussions around neoadjuvant therapy, molecular profiles, and resectability, explained Balazs Halmos, MD.

“We’re very fortunate now that surgery is not the sole approach in a way, even in early-stage disease,” said Halmos. “In the metastatic setting, the approach has been palliative treatment, where we’re hoping for control, not cure. But that language is shifting a little bit as of late, and it is shifting as a result of outstanding new choices being available for our patients.”

In an interview with OncLive^®, Halmos, director, Thoracic Oncology, director, Clinical Cancer Genomics, Montefiore Medical Center, discussed differences in the management of early- vs late-stage NSCLC and the erasure of single-modality therapy across the field.

OncLive^®: How would you define the differences in the management of early- versus late-stage lung cancer?

Halmos: The management is drastically different. The goal of treatment in early-stage disease is cure. We want to do our best to achieve the highest chance of cure for our patients and that involves definitive treatment [with] surgery or radiation.

The patient’s characteristics, as far as the particular stage of the tumor, will define what the best approach is. However, the main building blocks will be around surgery or radiation and will be dependent on the stage and the patient’s comorbidities, age, frailty and preferences.

We’ve seen more and more very solid data come out that stereotactic body radiotherapy [(SBRT) and surgery] can be very successful. Especially for the frail elderly [patient who has] significant lung disease and limited lung function, that provides now a really noninvasive and very successful approach.

It’s great to see the advances in terms of being able to provide that type of definitive treatment as well. As we move up in stage, neither surgery nor radiation is highly curative on their own. Therefore, we integrate other treatment options into the management, such as adjuvant chemotherapy for patients with resected higher-stage disease. That’s certainly the recommendation for most patients with stage II or IIIA disease after resection, but it can be a consideration for some of the larger, stage IB patients as well.

Now, we have seen great excitement about incorporating molecularly targeted therapy in the management of earlier-stage disease. The ADAURA study showed really dramatic results in terms of disease-free survival [DFS] benefit, which will likely yield an FDA approval in the coming months. As soon as that happens, it will be appropriate to at least discuss [that option] with our patients. It’s not going to be a mandatory guideline-driven treatment yet, since we’re waiting for an overall survival [OS] readout on the study, which might not be expected for a few years, but patients should hear about that option. If patients prefer to receive it, we should do our absolute best to provide that option [as much and as safe] as possible.

When will molecular testing become standard practice in the early-stage setting?

Up until now, there wasn’t truly a mandate to pursue molecular [or] immune biomarker testing in the earlier-stage setting. That is changing with the results of the ADAURA study. If you identify a patient with stage IB, II, IIIA disease, in particular stage II/IIIA, where the biggest benefit was seen, who harbors a tumor with an EGFR mutation, we might be able to offer them adjuvant treatment, yielding very significant benefits and delay the chance of recurrence. Hopefully, this will translate into an OS benefit as well.

Now, each of our institutions needs to look at our practices [and determine how we can] integrate molecular testing into that context. I’ve heard discussions that it will be difficult, and I sort of laugh at that, because you’re talking about a single gene—a gene that you test for every day in the metastatic setting. Therefore, there [should be] no difficulties whatsoever. We do this for patients with breast cancer all the time with hormone receptor, HER2 testing, etc. EGFR testing will be a mandate [in the near future].

Most likely from that experience, there will be other molecular subsets we might want to learn about, because maybe the benefits are just as important. Expanded testing will be appealing for our patients, especially as there are clinical studies that we can refer them towards dependent on particular biomarker alterations.

Immune biomarker testing is the other issue. PD-L1 testing is standard of care for patients with metastatic NSCLC, but it isn’t so in earlier stages of disease. Will it be? We’ll have to see the readout of many adjuvant and neoadjuvant studies. What we know from the PACIFIC study is that the approval of durvalumab [Imfinzi] is not dependent in the United States based on PD-L1 tumor proportion score [TPS].

At the same time, if you look at the data carefully, the benefits seem to be significantly less for the patients with a TPS score of 0. Clinicians will differ as to how they read into that data. Some clinicians feel that they want to know that information; I find it useful.

We still offer durvalumab to everyone, but in a way, maybe your enthusiasm will be less to push on with durvalumab in the face of AEs, if you know that the expected benefit might not be as much. For the balancing act, understanding what benefits you expect from a particular treatment your offering is helpful information. I’m very eager to learn about those clinical studies that might guide us in that direction as well.

How do you mitigate the toxicities of chemoradiation in preparation for the year of adjuvant durvalumab in the stage III setting?

As we move up into more locally advanced stages of disease, such as unresectable stage III disease, the standard treatment for many years has been concurrent chemoradiation. We have seen a major advance in that situation in that particular stage with the incorporation of immunotherapy, based on the outstanding results of the PACIFIC study. That’s now the standard of care for most of our patients with unresectable stage III disease: concurrent chemoradiation, many times, with a platinum/taxane doublet—but there are other chemotherapy choices available as well—followed by a year of adjuvant durvalumab. That yields much better results than [what we have seen] in the past.

Each year, we see a new update of the PACIFIC study. Currently, we just learned about the 4-year update. It does seem that the OS benefit stands at a 10% difference in terms of OS. We’re starting to believe that we’re curing an extra 10% of patients; that’s 1 out of 10 patients that we see in clinic. That’s a very important advance, and we want to make sure that we offer it to every appropriate candidate.

Also, we want to deliver our treatments in a way that our patients are able to make it to the point that they remain candidates for the immunotherapy portion of their treatment. It is very important to give very careful supportive care throughout concurrent chemoradiation, and potentially pull back at times when patients are struggling, especially in the chemotherapy part to make sure that they remain in reasonable shape to be able to receive and benefit from immunotherapy.

Fortunately, adjuvant immunotherapy is quite safe, but it’s not perfectly safe. Therefore, we also need to keep in mind that some patients will have immune adverse effects [AEs]. Especially in a post-radiation setting in patients with potentially poor lung function to begin with, pneumonitis is the most feared AE in this particular context. I want to make sure that our patients are not suffering from significant radiation pneumonitis. As we initiate immunotherapy, we want to monitor them carefully, and initiate appropriate treatment of pneumonitis or other immune AEs as soon as possible.

We are very fortunate now that there are so many great guidelines from the American Society of Clinical Oncology, and other organizations, to help the clinician, even with uncommon immune AEs, as to what the right steps are. We want to continue to look at that type of guidance but also build the right support in our institutions as to subspecialists, who we can lean on, in terms of nephrologists, gastroenterologists, pulmonologists, endocrinologists, and dermatologists to manage the most common immune AEs that we see in our practices. Therefore, you want to stay friends with your medicine subspecialists to make sure that you can call on them.

How should surgery be incorporated into the management of a patient with stage III disease?

There’s another less defined stage II disease, which is resectable stage III disease, and this is where [the approach is] in the eye of the beholder. It depends on so many different characteristics of the tumor itself, the tumor size, the invasion of nearby organs, and nodal involvement: Is a single station, or is it multi-station N2 involvement?

[It’s] things of that nature [that we have to consider], but there are also a lot of patient characteristics and physician preferences as well. Some treatment teams are very capable and skilled, and offer multimodality therapy with surgery incorporated into the management of a stage III patient. Some teams are less inclined, when in reality, we don’t have very firm data separating the outcomes with nonsurgical or surgical treatment in that particular context. It’s appropriate to have multiple options on the table in a way. We’re not sure when and how to find out which approach is superior.

We have definitely seen a lot of excitement now in the marginally resectable patients with the integration of potentially neoadjuvant treatment, such as neoadjuvant chemotherapy and immunotherapy. We’re thinking about the recent publications in Lancet by the team from Columbia University Medical Center of the NADIM study, which demonstrated very high chances of a major pathological response as well as a significant chance of a complete pathological response with a few cycles of neoadjuvant chemoimmunotherapy. Large randomized phase 3 studies are ongoing, and we should support them to find out if that particular treatment approach should become the standard of care.

How should resectability be defined?

Resectability is in the eye of the surgeon. I’m very careful. I never say the word “unresectable” unless a surgeon said unresectable before me. Medical oncologists need to recognize and [be] aware [of where our] limits stand to defining surgical cases. That being said, for certainly entry disease multi-station bulky, N2 disease, most institutions will view those patients as unresectable. The discussion is much more important in a way for patients with limited N2 disease, single-station disease, which surgically, is definitely resectable.

Is there a benefit of the surgical intervention in some of these patient subsets where it can be done, but we don’t have high level data to argue that it should be done? This is where we need to [look at other factors] for this discussion; there are a lot of other things besides resectability, such as the patient’s particular features and the risk of surgery. For someone who is very elderly, frail, has borderline lung function, cardiac disease, maybe the same conversation would go in a very different direction and factor the patient into the discussion. All those issues need to be discussed and considered.

The technical skill and familiarity with the treatment team matters as well. In some institutions, certain things are done more frequently than others. If there are high level data supporting one practice, we absolutely should support it. However, if both approaches can be appropriate, then that familiarity should play into [the decision] as well.

How do your treatment approaches change in the metastatic setting?

Now, we can learn about the molecular profile of the patient’s tumor much better, and we can match targeted therapies. Currently, we have 8 validated targets, and the ninth, KRAS, is just about to catch up. This is why we want to make sure that expanded molecular testing is done for each of these patients.

We just learned from studies of ALK-rearranged lung cancers that frontline agents, such as alectinib [Alecensa] can yield a median OS that surpasses 5 years, and that’s an amazing number to state for somebody who started in this field with the average patient with metastatic lung cancer patient surviving 1 year. Our patients are doing better and they’re living longer, and maybe some of our patients are able to achieve such durable control of their cancers as a result of targeted therapy, so we can start thinking about long-term disease control.

With the introduction of immunotherapy, the word “cure” has been introduced into our vocabulary. Anti–PD-1/PD-L1 agents have really revolutionized how we manage metastatic NSCLC. Some of our patients, especially patients falling into very specific profile with the PD-L1 biomarker being very strongly expressed, can achieve a high rate of not just remissions, but lasting remissions. In fact, what we’re seeing from the early studies of these agents, especially pembrolizumab [Keytruda] and nivolumab [Opdivo], is that even patients who might have stopped the drug, might not see a recurrence of their disease for a number of years after stopping any systemic management. We’re cautious about using that word in a way, but we’re starting to kind of peek at these data and feel that some of our patients are able to achieve such long-term disease control that they might not require systemic treatment at all, at least for extended periods of time.

We still have many patients, though, who are not doing this well, so we should continue to build upon it. That’s where our research has to continue. The number of research studies ongoing to try to enhance the benefit from our immunotherapies and targeted therapies is just mind boggling. I’m very hopeful that many of those approaches will be successful over time, but they cannot be successful unless we get our patients on clinical studies. All of us in this field have to continue to come to work ready to offer our best studies to our patients.