Therapy for Stage IV NSCLC Without Driver Alterations: ASCO Living Guideline Update 2026.3.0 Part 1

Dr. Joshua Reuss is back on the podcast to discuss the full update to the living guideline on stage IV NSCLC without driver alterations. He discusses the new evidence and how this impacts the latest recommendations on first-line and subsequent therapeutic options. Dr. Reuss emphasizes the need for shared decision-making between clinicians and patients. He shares ongoing research that the panel will review in the future for further updates to this living guideline, and puts the updated recommendations into context for clinicians treating patients with stage IV NSCLC. Read the full living guideline update "Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2026.3.0" at www.asco.org/thoracic-cancer-guidelines"

TRANSCRIPT

This guideline, clinical tools and resources are available at www.asco.org/thoracic-cancer-guidelines. Read the full text of the guideline and review authors' disclosures of potential conflicts of interest in the Journal of Clinical Oncology, https://ascopubs.org/doi/10.1200/JCO-25-02825

Brittany Harvey: Hello and welcome to the ASCO Guidelines podcast, one of ASCO's podcasts delivering timely information to keep you up to date on the latest changes, challenges, and advances in oncology. You can find all the shows, including this one, at asco.org/podcasts.

My name is Brittany Harvey, and today I am interviewing Dr. Joshua Reuss from Georgetown University, co-chair on "Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2026.3.0."

It is great to have you back on the show today, Dr. Reuss.

Dr. Joshua Reuss: Happy to be here, Brittany.

Brittany Harvey: Just before we discuss this guideline, I would like to note that ASCO takes great care in the development of its guidelines and ensuring that the ASCO Conflict of Interest Policy is followed for each guideline. The disclosures of potential conflicts of interest for the guideline panel, including Dr. Reuss who has joined us here today, are available online with the publication of the guideline in the Journal of Clinical Oncology, which is linked in the show notes.

Dr. Reuss, this living clinical practice guideline for systemic therapy for patients with stage IV non-small cell lung cancer without driver alterations is updated on an ongoing basis. So, what prompted this latest update to the recommendations?

Dr. Joshua Reuss: Our committee is tasked with making routine updates to the living guidelines and really keeping them living, right? So, evaluating new data as it is coming in to see, is this practice changing? Is this data that should inform and potentially alter our guideline recommendations so that practitioners and other care providers could really make the best treatment decisions for their patients?

So that is something that happens on a more routine basis, but periodically, we are tasked with performing a more comprehensive update of our guideline where we really evaluate every one of our point recommendations, the data associated with these recommendations, to be sure that these are up to date, these are comprehensive, and to see if we need to alter anything in the language of these updates.

Brittany Harvey: Excellent. Thank you for providing that background. And yes, this is truly a comprehensive update that goes through all the latest literature. Given that, I would like to review what has changed and what is new in the recommendations. So, what are the updated recommendations on first-line therapy for patients with stage IV non-small cell lung cancer without driver alterations?

Dr. Joshua Reuss: So there are two main guidelines that we recommend from this panel. One is a driver mutation-positive guideline and the other is a driver mutation-negative guideline. And I think on first blush, one might look at kind of the recent flurry of approvals and new data and say, well, all the excitement, you know, is in the driver mutation-positive guideline.

But I would say that the driver mutation-negative guideline is equally as important and really has several unique challenges associated with it. You know, first and foremost is that there are really a multitude of regimens that can be considered for any one patient. And how to choose between one can be quite difficult and a stressful challenge that clinicians can have, particularly since there are really no randomized studies comparing these regimens in a head-to-head fashion.

In addition, you know, these guidelines are really broken down by two key factors. One is disease histology, so namely squamous versus non-squamous histology. And the other is PD-L1 status, broken down into one of three tertiles: PD-L1 high, which is greater than or equal to 50% expression; PD-L1 low, which is 1% to 49% expression; and then PD-L1 negative or unknown.

So what you are really looking at, if you do that math, is really six unique patient subpopulations where we need to make a recommendation on one of the multitude of treatment regimens that is approved. And what that means is you are oftentimes really looking at subset and sub-subset level data to help inform clinicians in their treatment decision making, which can be quite challenging because as those small subsets of data is more and more parsed, there are many confounders that can be interjected there. And so I think the committee is tasked with really quite a challenge in terms of how to really communicate and broadcast that data in a way that informs clinicians in making a decision on what is the right treatment for their patient.

Brittany Harvey: Absolutely. It can be challenging to interpret that subgroup data across several different studies that are reporting on different regimens and different outcomes. And I appreciate you mentioning the driver mutation-positive guideline as well. Listeners can check out the companion episode with Dr. Puri for more information on what is changed in the driver mutation-positive guideline.

Based on that primer, what is new for first-line therapy for patients with stage IV non-small cell lung cancer without driver alterations?

Dr. Joshua Reuss: Even though I will say there is not a lot of new trial data that was incorporated into this guideline, there were some updates and just some meaningful long-term data that we incorporated. I think first and foremost, there is a new top-level recommendation in this guideline pertaining to molecular testing, which is absolutely critical in both the driver mutation-positive and driver mutation-negative space. I think we tend to think that, oh, well, molecular testing really only pertains to then finding a driver mutation. But the lack of a mutation is absolutely critical as well, right? Because that is what leads us down the mutation-negative pathway.

We also need this molecular testing to assess PD-L1 status. We are seeing emerging data on molecular mutations that might confer resistance to certain immunotherapy-based strategies. So the committee felt strongly that a recommendation on molecular testing is critical to include in both the driver mutation-positive guideline and the driver mutation-negative guideline.

I will also say that we are now seeing five and six-year updates from some of the landmark trials of immunotherapy in driver mutation-negative non-small cell lung cancer. It is really incredible to see that in some of these trials, we are seeing very impressive durability of the treatment in the patient subsets that we are commenting on. In others, perhaps that durability is less clear, and I think that leads to challenges in making a recommendation on any one particular regimen. And I think that is nowhere more clear than in the squamous subset. I think that was one perhaps subtle change that is in this guideline where, particularly in the PD-L1 negative squamous population, the committee felt that no one regimen really was worthy of standing above the others.

Sometimes I think it is important to really champion one unique regimen if we feel that the data is there to support it. But I think it is equally important to list multiple regimens where the data is less clear. I think another point is that while perhaps there were no new regimens that we have added or that led to other clear changes in the prioritization of one regimen over another, there are other unique data subsets that I think come into play in making a decision and that really are important when looking at the discussion on any one recommendation from this guideline.

For example, we know there is emerging data on perhaps the significance of molecular alterations in KEAP1 or STK11 and how that might influence frontline decision-making. You know, there is not a prospective phase III trial in this population, but I think we still need to use that data in certain scenarios to make recommendations for a particular patient.

Another example of a trial that, again, did not change our recommendations, but I think one can incorporate in their decision making is the KEYNOTE-598 trial. Now, this is not a new study, but what it studied was pembrolizumab versus pembrolizumab plus ipilimumab in a PD-L1 high subset, and found that the addition of ipilimumab to pembrolizumab in the PD-L1 high population did not significantly improve clinical efficacy.

And so while pembrolizumab plus ipilimumab is not an approved regimen, it is hard to extrapolate that to our combination treatments that are approved. I think some clinicians might find that data valuable when making a frontline treatment decision on a patient who has PD-L1 high status. So a bit of a whirlwind tour, but I think there are still multiple factors that went into this guideline that are important to review when making treatment decisions for any one patient.

Brittany Harvey: Absolutely. I think what you just mentioned in having that upfront molecular testing is really key for individualized patient care. And the evidence summaries that you provide in addition to the recommendations are really important for clinicians to be able to refer to as they are making decisions in their clinic.

So then beyond those changes for first-line therapy, what is updated for second-line and subsequent therapies?

Dr. Joshua Reuss: For second-line and subsequent therapies, we did see one new treatment recommendation join these ranks, and that was telisotuzumab vedotin. Telisotuzumab vedotin, quite a mouthful. That is an antibody-drug conjugate. I like to think of that as smart chemotherapy, targeted chemotherapy, where you are trying to utilize some aspect of a marker that is selectively expressed or overexpressed on the cancer surface to then shepherd in the anticancer molecule, a highly potent chemotherapeutic in the case of currently approved antibody-drug conjugates, to exert antitumor killing effect.

So in this case, the antibody-drug conjugate telisotuzumab vedotin targets MET overexpression. So telisotuzumab is an antibody targeting MET, and that is conjugated to an MMAE highly potent chemotherapeutic payload called vedotin. So we know MET can be selectively expressed and overexpressed in non-small cell lung cancer in both driver mutation-positive and mutation-negative subsets.

The data that led to this approval was from the phase II LUMINOSITY trial which evaluated telisotuzumab vedotin, or Teliso-V, in many subsets. But the subset that really showed promise and was expanded was the EGFR wild-type, non-squamous, non-small cell lung cancer population with MET overexpression. And so in 78 patients with high levels of expression, the response rate here was 34.6%, median progression-free survival of 5.5 months, and a median overall survival of 14.6 months. With an overall acceptable safety profile; grade 3 or higher adverse events, neuropathy was perhaps the most common at 7%, also increased ALT at 3.5%, and pneumonitis at 2.9%.

Now this was phase II data that led to an accelerated approval. There is an ongoing phase III study randomizing patients with high expression to Teliso-V versus docetaxel. That is the phase III TeliMET study. But it is nice that we now have another option for patients, perhaps a more biomarker-directed option with, again, this MET overexpression. And again, it further reinforces the importance of molecular testing in patients with traditionally driver mutation-negative non-small cell lung cancer, whether that is upfront or at progression, and in particular utilizing immunohistochemistry to assess MET expression in these patients.

And this does join another ADC that we had previously made an update in our recommendation, which is trastuzumab deruxtecan, which is approved for those patients with HER2-overexpressing non-small cell lung cancer. So just again to reiterate the importance of molecular testing in patients both at the outset of their treatment and upon progression on frontline therapy.

Brittany Harvey: Definitely. It is great to have this new antibody-drug conjugate join the treatment options, and as you mentioned, very important in this case to have that molecular testing done at the outset and at progression.

So then in your view, what should clinicians know as they implement this living guideline, and how do these changes impact patients with non-small cell lung cancer?

Dr. Joshua Reuss: Because there are so many different regimens that one can consider for any one patient, I think it is easy to become overwhelmed and stress on, "Am I making the right choice for my patient?" And I think one of the key take home points is that in many cases, there is no one right regimen. And I think one has to weigh several factors. It is the treatment schedule. It is the toxicity profile. It is the molecular profile of the patient. It is the patient preference. You know, there are so many factors here.

And I would like to draw the reader and viewer's attention to an important section of these guidelines, particularly the Patient and Clinician Communication section, where we have a box focused on discussion points between patients and clinicians, which I think focuses on several of the high-level points that one can emphasize in making these decisions, ranging on things from: what are the goals of the treatment? What are the risks and benefits to any one approach? What are comorbidities that should be factored in? Common concerns, toxicity management, clinical trial consideration. All of these factors that I think are incredibly important in making that frontline treatment decision and implementing a regimen that both the clinician and, more importantly, the patient feels comfortable with.

Brittany Harvey: It is really important that there is shared decision-making in these scenarios. And I think that patient-clinician communication section can tease out some of those preferences from the patient end and talk through the risks and benefits of different regimens as well.

As we mentioned at the top of this episode, this guideline is a living guideline and updated on an ongoing basis. So what is the panel examining and keeping an eye on for future updates to this guideline?

Dr. Joshua Reuss: So I think there are a lot of exciting new therapies and more up-to-date trials that we are anxiously awaiting the results of on our committee, and I think the oncology community in general is awaiting the results of. When we will have these results, I think, is a bit of an open-ended question, but I can give some insight on several of the trials that our committee is really keeping a close eye on.

One that we have mentioned for several guideline iterations is the ECOG-ACRIN INSIGNA trial. This is a phase III clinical trial comparing pembrolizumab versus pembrolizumab plus carboplatin and pemetrexed chemotherapy in PD-L1 positive, non-squamous, non-small cell lung cancer. We talk about there being different regimens that can be considered in PD-L1 positive and PD-L1 high subsets, namely immunotherapy alone or immunotherapy plus chemotherapy, but there is no direct head-to-head comparison here. So this trial hopefully will answer that question. It has now finished accrual.

There are other very interesting molecules and trials. I think another interesting compound is ivonescimab. This is a PD-1/VEGF bispecific antibody that is currently approved in China as monotherapy in patients with PD-L1 positive non-small cell lung cancer based off of the HARMONi-2 trial, where the progression-free survival of this bispecific antibody, ivonescimab, appeared superior to pembrolizumab. And we are looking closely at ongoing trials to see if these results will be replicated in an ex-China population. And if so, I think it could have a real impact and change on our guidelines.

Still other very interesting things. There are obviously confirmatory studies for antibody-drug conjugates, such as the TeliMET study that I alluded to earlier, and many promising antibody-drug conjugates, both bispecific and trispecific antibody-drug conjugates, that hopefully can inform practice.

And then there are several unique subsets of populations that I think we now are utilizing data on to make decisions, but a lot of that is retrospective in small subsets where we do not have that prospective data. And there are several trials ongoing in some of these subsets to try to gain clarity on what regimen may be the best for patients.

One example is the phase III TRITON trial, which is looking at comparing CTLA-4 containing regimen, particularly the POSEIDON regimen of durvalumab plus tremelimumab and chemotherapy, versus the KEYNOTE-189 regimen, which is pembrolizumab plus carboplatin and pemetrexed, in patients with non-squamous, non-small cell lung cancer that have alterations in either KRAS, KEAP1, and/or STK11. There is a lot of both preclinical and clinical data to suggest that patients with these alterations in STK11 and KEAP1 may be more resistant to a PD-1 based treatment approach, and perhaps the incorporation of CTLA-4 can lead to a more meaningful response in this unique subset. Obviously, that data, it is retrospective, it is in small subsets. And when you add in a CTLA-4 molecule, you are also introducing greater risk for toxicity. So this trial is going to be very important in elucidating: is there a benefit in that unique subset? Does that data that we see retrospectively in this small subset hold true when evaluated in a prospective fashion?

So while our guideline, our most recent comprehensive panel update, may not have had a lot of new data in it that has influenced frontline treatment decision-making, I think the future is bright and there are a lot of novel studies and novel treatments on the horizon that will hopefully improve the outcomes for our patients.

Brittany Harvey: Absolutely. We will look forward to the results of those ongoing trials to provide more options and particularly clarity for patients with non-small cell lung cancer and to inform this guideline and its many updates to come.

So I want to thank you so much for your work to rapidly and continuously update this guideline, and thank you for your time today, Dr. Reuss.

Dr. Joshua Reuss: Thank you so much.

Brittany Harvey: And finally, thank you to all of our listeners for tuning in to the ASCO Guidelines podcast. To read the full guideline, go to www.asco.org/thoracic-cancer-guidelines. You can also find many of our guidelines and interactive resources in the free ASCO Guidelines App available in the Apple App Store or the Google Play Store. If you have enjoyed what you have heard today, please rate and review the podcast and be sure to subscribe so you never miss an episode.

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