Martins Makes Sense of the Complicated Frontline NSCLC Treatment Landscape

Renato G. Martins, MD, discusses the many up-front approaches that have emerged in NSCLC, remaining questions to address with future efforts, and novel combinations under exploration.

Treatment with immunotherapy earlier on in the treatment journey for patients with non–small cell lung cancer (NSCLC) who do not have a targetable mutation has proven to be very beneficial, according to Renato G. Martins, MD, but the challenge now lies in understanding when to use a chemoimmunotherapy approach versus a dual immunotherapy regimen.

“When it comes to the average patient, excluding those with targetable mutations because they have a different biology, it seems that [treatment with] immunotherapy early on is a huge plus,” said Martins, medical director of Thoracic, Head and Neck Oncology at Seattle Cancer Care Alliance. “This is incredibly hard to prove, for obvious reasons, but there is some evidence to suggest that immunotherapy may actually change one's response to subsequent therapies. This would be another reason to expose patients early on, especially if you are changing the natural history of the disease.”

In an interview with OncLive® during the 2020 Institutional Perspectives in Cancer webinar on Lung Cancer, Martins, who is also professor and medical director of Outpatient General Oncology and Hematology-Oncology at the University of Washington School of Medicine and a professor in the Clinical Research Division at Fred Hutchinson Cancer Research Center, discussed the many up-front approaches that have emerged in NSCLC, remaining questions to address with future efforts, and novel combinations under exploration.

OncLive®: Beyond PD-L1 expression, are any biomarkers under exploration to help determine which patients should or should not receive immunotherapy?

Martins: Aside from PD-L1, it isvery hard to exclude someone from immunotherapy at this point in time. There is SDK11, which could supposedly predict a poor response to immunotherapy. However, until we have a biomarker for which we are convinced that we can exclude patients from therapy due to its presence, PD-L1 remains the holy grail. We are just not there yet.

Do you believe the field is shifting toward more combination approaches versus monotherapy? Are there concerns with regard to toxicity?

Over the next few years, we will see more immunotherapy combinations comprised of agents that are not even approved yet. I suspect that we will also see higher response rates as we add different immunotherapy agents; hopefully, this will not [come with] a substantial increase in toxicity. In patients with lung cancer, this is rare, but it could also be devastating.

Patients might not necessarily develop fatal toxicities, but long-lasting toxicities; these effects could have a serious impact on their quality of life.

Furthermore, cellular immunotherapies are being combined with checkpoint inhibitors.

As I simply explain to patients, we’re trying to potentiate the effect of the angry cells against the tumor by adding checkpoint inhibitors to the mix.

It's almost overwhelming to think about the amount of research that will need to happen over the next few years for us to be able to understand the potential of the therapies we currently have.

What are some of the data to support the use of immunotherapy earlier on in the treatment journey?

There are data suggesting that, if you see benefit with immunotherapy in combination with chemotherapy up front, it’s better than seeing it sequentially. Also, studies from 2 different institutions looked at subsequent therapy. So, this is after you stop immunotherapy, and then you give second- or third-line therapy.

In the best way they could, they tried to match patients before immunotherapy was available and after they received immunotherapy. It seems that the duration of treatment for subsequent lines of therapy is longer, which would be an indirect way of evaluating clinical efficacy. Do you change the natural history to a more indolent disease, even when patients have stopped responding to immunotherapy, or even perhaps if they never responded?

The first article on this topic was published in the New England Journal of Medicine [years ago]. We’re about 8 years into this research, and there is still a lot to learn. However, I’m certainly in favor of early exposure, as opposed to late exposure.

How do you determine when to use a dual immunotherapy combination versus a chemoimmunotherapy approach? What are some of the data that you use to support your decision?

Two trials have examined the role of the ipilimumab/nivolumab combination.

The first trial had a very complicated design. In this trial, investigators compared ipilimumab and nivolumab with chemotherapy and demonstrated that [the former] was superior [to the latter].

Although the FDA has not yet approved this regimen for patients who are PD-L1 negative, the benefit seen with the combination appears to be upheld across all levels of PD-L1 expression. We now know that this dual immunotherapy approach is better than chemotherapy, but is it better than chemoimmunotherapy?

For patients who are not great candidates for chemotherapy for reasons such as organ dysfunction rather than a lack of functional capacity, the [dual immunotherapy] combination might make sense. The same holds true for a patient who refuses the administration of chemotherapy, for whatever reason.

In another trial, investigators administered a couple cycles of chemotherapy combined with the same immunotherapy combination [of ipilimumab/nivolumab]. That approach also proved to be superior to chemotherapy alone. We must now determine the role of these 2 additional cycles of chemotherapy, and when that approach would be most appropriate.

[It might make sense to use this] approach when we believe that the window of opportunity for administering chemotherapy may be closing. For patients who have a PD-L1 expression of around 50%, but also have liver disease and a borderline functional capacity for chemotherapy, meaning that if the patient gets worse, chemotherapy may not be an option anymore, then I would definitely treat them with chemoimmunotherapy. The response rate for immunotherapy alone, even in patients with high expression, is in the range of 40% to 50%, while the response rate to chemoimmunotherapy may 60% or higher.

With all of these immunotherapy combinations, do you foresee chemotherapy retaining its role in the up-front setting?

As an increasing number of immunotherapy combinations emerge in the landscape, we will need to determine the role of chemotherapy. Are we going to see response rates that are high enough [with the immunotherapy regimens] that it will not make sense to administer up-front chemotherapy?

This is a whole new landscape but it’s exciting to see how much progress has been made.

I feel like we just climbed a big mountain and we are starting to see the valley down below. Things will continue to just get better and better.

Are any emerging efforts under investigation that you are excited about?

At the 2020 ASCO Virtual Scientific Program, we saw interesting data with a new combination targeting CD47 [that was examined] in other diseases; it seems quite promising. What will be its role in lung cancer? By itself, it may not have much of a role; however, it may have quite a significant role in the context of immunotherapy combinations. It's very hard to predict the future standard of care in this space. I try to convey this message to patients.

This may be somewhat controversial, but I personally find it hard to make survival predictions for someone who is diagnosed today. If we can keep their disease under control for several years with what we have today, what will we be available to offer them in 3 years? No one knows. I believe this is an important message to convey. Ultimately, this is a serious diagnosis and, if things go poorly, the prognosis could be terrible. However, there is always hope that better therapies will come, and patients will be able to derive more benefit from them.