Biomarkers for Frontline Immunotherapy Pose Obstacles in NSCLC

John A. Kosteva, MD

Although PD-L1 has been coined an “imperfect biomarker” and tumor mutational burden (TMB) is still investigational in many ways, the adoption of immunotherapy agents into frontline treatment continues for patients with non—small cell lung cancer (NSCLC), despite the inability to accurately select patients, said John A. Kosteva, MD.

“We’re still trying to tease out which patients might be best for combination immunotherapy, single-agent immunotherapy, and chemotherapy plus immunotherapy,” he explained. “Whether we use TMB, PD-L1, or comorbidities, we still have some work to do to sort that out over the next couple months to years.”

Until these assays are further refined, Kosteva said that the decision to use immunotherapy often lies in a physician’s ability to discern a patient’s disease burden and symptomatic disease from more indolent NSCLC.

OncLive: What are the criteria that qualify a patient for immunotherapy?

Are physicians relying less on PD-L1 and more on TMB these days?

How do you determine whether to give single-agent or combination immunotherapy?

In an interview during the 2018 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Kosteva, clinical assistant professor of medicine, University of Pennsylvania School of Medicine, Abramson Cancer Center, discussed the adoption of immunotherapy into the treatment paradigm for patients with NSCLC.Kosteva: When we meet patients for the rst time and do their initial staging, we are always adding molecular and PD-L1 studies to help us sort out the best treatment options. With any immunotherapy drug, we’re always looking for any contraindications. A patient who had an organ transplant might be at risk for rejection or a patient with poorly controlled autoimmune disorders on high-dose steroids might sway us one way or another. Based on some of the recent studies from the 2018 AACR Annual Meeting and the 2018 ASCO Annual Meeting, we’re pushing immunotherapy drugs to the frontline setting for most patients across the board with lung cancer.We’re going to be looking more at some of the immunotherapy combinations with TMB. Right now, it’s not quite ready for prime time in the community yet. It is a pretty specific test, but a lot of different genetic testing companies are looking at how it can help clinicians sort out TMB. It’s certainly something we are working on in our health system to see how we can measure [TMB] and make this part of routine testing.Right now, PD-L1 is still the best test we have to help sort that out. Patients with 50% or higher PD-L1 expression might be eligible for single-agent pembrolizumab (Keytruda). It’s still a case-by-case basis. It’s a whole new world that we weren’t used to a couple months ago. We are still trying to sort out the patients who will be the most likely to benefit from single-agent immunotherapy versus chemotherapy/immunotherapy or immunotherapy/immunotherapy.

If a patient has PD-L1 expression greater than 50% and is eligible for frontline single-agent pembrolizumab, I look at their disease burden to see how symptomatic they are. [I have to determine] if this is a patient who needs to get their disease under control quickly with a rapid response. Patients with fairly symptomatic disease and high TMB are the patients you want to put a priority on getting a high response rate with frontline treatment. These are the patients you’re concerned might not have a good shot with second-line therapy. Therefore, you want to try to go “all in” now because your first-line of treatment is going to be your best and only chance to get their disease under control. These are the patients I would give triplet therapy with pembrolizumab and standard chemotherapy to.

What is your opinion on the chemotherapy and immunotherapy combinations?

I might be more inclined to use single-agent pembrolizumab in a patient with pretty indolent disease. These would be the patients who are not very symptomatic, have more [of an] incidental low TMB, and maybe other comorbidities. They may be older, so you may be concerned about the toxic side effects of chemotherapy. Maybe it’s a patient who is pretty chemotherapy averse and doesn’t want the side effects of it. Perhaps they have had family members and friends who have had bad experiences.Overall, it’s very exciting. Lung cancer has changed a ton over the last 2 months with the 2018 AACR Annual Meeting and the 2018 ASCO Annual Meeting. What I learned about oncology in NSCLC in fellowship 10 years ago is completely obsolete now. It’s great to have options. When you look at the survival curves over the last decade, we have been pushing those numbers out at multiple increments. We’re helping our patients a lot more now than we did before.

What is the importance of reporting immune-related adverse events?

If a patient presents with a driver mutation, what is your first choice of therapy?

Are there any clinical trials in this space that you’re excited about?

Will single-agent chemotherapy become obsolete?

We’re still trying to gure out how to use those drugs. There are a lot of factors. We are still trying to tease out which patients might be best for immunotherapy/immunotherapy, immunotherapy only, and chemotherapy/immunotherapy. Whether we use TMB, PD-L1 testing, or comorbidities, we still have some work to do to try to sort that out over the next couple months to years.These are different side effects than what we’re used to seeing with traditional chemotherapy. It’s a different paradigm where you’re not paying as much attention to complete blood cell counts and nausea. We are trying to teach our patients about these drugs and make them aware of what to look out for. Every time these patients come in for treatment, we have nurses involved [to help] educate and empower them with what to look for.I’m still going after the driver mutation first. If you look at the efficacy of tyrosine kinase inhibitors (TKIs) [in targeting] those mutations, we’re seeing better progression-free survival, response rates, and toxicity profiles. That’s still kind of my go-to choice. When we start seeing resistance to those drugs and you’ve exhausted the TKIs and [are] moving on to what would have been platinum-doublet chemotherapy, that’s where we’re starting to use immunotherapy now.The whole oncology world, [especially] in lung cancer, is really changing. There is a lot going on [that we’re] trying to sort out. We still need to answer the question of which patients are the most likely to benefit from these different combination approaches. [We also need to establish how to] use these tests to dictate what the best treatment options are going to be for certain patients.It’s fading away pretty quickly with some of the KEYNOTE studies that we’re seeing. We’re using it more after immunotherapy [for] second-line treatment and beyond for those nondriver mutation patients. Perhaps in the future, we will gure out [how to] use immunotherapy plus chemotherapy in the first-line setting and maybe a different immunotherapy plus chemotherapy with a different mechanism in the second-line setting. That may be the answer in the future.