Therapy for Stage IV NSCLC Without Driver Alterations: ASCO Living Guideline Update 2025.1 Part 1

Dr. Lyudmila Bazhenova is back on the podcast to discuss the latest update of the living guideline on therapy for stage IV NSCLC without driver alterations. She shares the studies the Expert Panel reviewed in the first- and second-line settings, including NIPPON, HARMONi-2, and DUBLIN-3. Although these studies do not impact the existing guideline recommendations, Dr. Bazhenova provides context and comments on ongoing trials that will influence the next iteration of the living guideline. Read the full living guideline update "Therapy for Stage IV Non-Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2025.1" 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-25-01062

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'm interviewing Dr. Lyudmila Bazhenova from University of California San Diego Moores Cancer Center, co-chair on "Therapy for Stage IV Non–Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, Version 2025.1."

It's great to have you back on the show today, Dr Bazhenova.

Dr. Lyudmila Bazhenova: It's my pleasure to be here.

Brittany Harvey: And then before we discuss this guideline update, I'd 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. Bazhenova, 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.

So then to dive into the content here, Dr. Bazhenova, 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 continuous basis. So what prompted this latest update to the recommendations?

Dr. Lyudmila Bazhenova: Living ASCO guidelines are designed to keep pace with rapidly evolving evidence that impacts treatment of our patients with lung cancer. As a committee, we are tasked with regular review of the published literature and determine if the new data warrants changes to existing recommendations. So in this recently published update, we evaluated new trials related to treatment of patients with metastatic lung cancer without driver alterations.

Brittany Harvey: Excellent. Thank you for that explanation of the process.

So, you just mentioned that the panel reviewed new trials for this update. So, which particular updated evidence did the panel review on first-line treatment options for patients with good performance status across histology and PD-L1 expression status, and how did this impact the recommendations?

Dr. Lyudmila Bazhenova: For the first-line treatment option for patients without driver alterations, two studies met our criteria for review. One was the NIPPON trial from Japan, the second was the HARMONi trial. None of those two trials resulted in change in our guidelines, but I think they are giving us some additional information that would be useful for the way we treat patients with non–small cell lung cancer without driver alterations. For example, if we take those patients, we currently have several treatment options as a first line. One is monotherapy immunotherapy. You can give pembrolizumab as an example, and that was based on the KEYNOTE-024 and KEYNOTE-042 trials. Then we have a platinum doublet plus immunotherapy, and there are several trials that did that pathway. And then we have also an option of giving our patients dual IO immunotherapy combination, such as CheckMate 9LA and POSEIDON.

At this point, we do not have any randomized trials comparing those three treatment modalities head-to-head. And the NIPPON trial was interesting to us because it was the first trial to compare CheckMate 9LA regimen, which is again, dual immunotherapy plus chemo, versus KEYNOTE-189 or KEYNOTE-407, which is a chemotherapy plus immunotherapy. And as a result of the study, while chemotherapy plus ipilimumab-nivolumab led to numerically higher overall survival, the difference was not statistically significant. And what is concerning in that trial is that we saw a higher number of treatment-related death occurring in nivolumab and ipilimumab arm compared to the pembrolizumab-chemotherapy arm. As a matter of fact, the trial was terminated early because of the increased risk of death. If you look at the treatment-related death in CheckMate 9LA, the 9LA study reported the treatment-related death to be 2%, and then in the NIPPON trial, the treatment-related death was 7%. Why is that happening? It's really difficult to say. The study was done in Japan. Maybe there is some pharmacogenomic differences between global population and Japan population. But certainly the higher rate of adverse events needs to be taken into account.

Another interesting thing about this trial is that it did not show any differences in a subset analysis for patients with squamous histology as well as PD-L1 negative tumor. So while this does not change our current guidelines and CheckMate 9LA treatment still remains an appropriate treatment option, it kind of raises the possibility that this combination could be associated with a higher toxicity. And we do have a randomized US-based trial that is ongoing, and we are hoping that eventually we will be able to answer that question after the trial will be completed.

The second trial we reviewed is HARMONi-2. So HARMONi-2 was a randomized, double-blind study which is conducted primarily in China, looking at bispecific PD-L1 and VEGF antibody called ivonescimab. And that took patients who were PD-L1 positive, as defined as more than 1% expression, and patients were randomized to pembrolizumab versus bispecific ivonescimab. And the study was positive. It showed improvement in median progression-free survival of 11 months versus almost 6 months in bispecific versus pembrolizumab. There were, however, higher grade 3 events in the ivonescimab arm. At this point, we are not changing our recommendations because this trial was done in an ex-US population, and we are awaiting a similar trial ongoing in the United States before we change recommendations and decide if ivonescimab needs to be included in our guidelines.

Brittany Harvey: This context is very helpful when clinicians think through the data behind these options. And it's important that the panel reviews this evidence, even if it doesn't prompt a change to the recommendations. And we'll await results of those trials that you mentioned to further inform this guideline.

So then beyond those studies for first line, what updated evidence did the panel review for second-line and subsequent treatment options for patients with good performance status, and how did this impact the recommendations?

Dr. Lyudmila Bazhenova: So for second line, only one trial met the criteria, and that was DUBLIN-3. DUBLIN-3 is a phase 3 single-blind randomized trial comparing docetaxel versus docetaxel plus plinabulin. And the study enrolled patients with second or third line. They have to have had platinum-based chemotherapy and progressed. Plinabulin is an interesting compound. It's a small molecule tubulin binder that prevents polymerization of tubulin and appears to impact dendritic cell maturation and T-cell activation. This study enrolled 559 patients, randomly assigned them to two groups. And one important information about this study is that was a study that was envisioned before immunotherapy became a standard mainstream treatment for first-line therapy. And only 20% of patients had prior PD-1 exposure. So therefore, the results of that study need to be taken into context of this population no longer existing in the United States because we use PD-L1 inhibitors in the first line.

And we saw that interesting in the plinabulin arm had lower rates of neutropenia but higher rates of serious adverse events. And at this point, we are not changing our guidelines for mainly two reasons. Number one, low number of patients that received prior treatment with first-line immune checkpoint inhibitors, as well as a modest overall survival benefit of this trial.

Brittany Harvey: Understood. I appreciate you describing that study as well and why that evidence didn't prompt a change to those particular recommendations.

So then, what should clinicians know as they implement this living guideline, and how does this new evidence impact clinicians and patients?

Dr. Lyudmila Bazhenova: At this point, none of the studies that we reviewed resulted in a change in guidelines. We are still waiting for more global results from some of the studies that I highlighted. It shows that there's still a lot of questions we need to be answering in those patients. And I'm hoping that with future clinical trials, we will be able to definitively maybe recommend one treatment over another. But at this point, all the treatments that I mentioned before remain appropriate for patients with stage IV non–small cell lung cancer without driver alterations.

Brittany Harvey: Definitely. And then you just mentioned that there's still a lot of outstanding questions in this field. You've mentioned a couple different studies where we're awaiting evidence. Beyond those that you already mentioned, what is the panel examining for future updates to this living guideline?

Dr. Lyudmila Bazhenova: Right now, our next task is to come up with a full guidelines update. ASCO have certain rules for the guidelines committee members. And so we are gearing for a full guideline update, which hopefully will be ready by the end of 2025.

Brittany Harvey: Excellent. We'll look forward to that full update of the living guideline, and we'll still await results of these ongoing trials to further inform this living guideline.

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

Dr. Lyudmila Bazhenova: My pleasure.

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, which is available in the Apple App Store or the Google Play Store.

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