Navigating Complexity: Key Updates to ASCO's Living Guidelines for Stage IV Driver Mutation–Negative NSCLC

For clinicians managing patients with advanced non–small cell lung cancer (NSCLC), keeping pace with the rapidly evolving treatment landscape is no small task. ASCO's living guidelines aim to ease that burden by providing continuously updated, evidence-based recommendations, and the latest update to the stage IV NSCLC guideline for driver mutation–negative disease brings several noteworthy changes.¹ Joshua Reuss, MD, a thoracic medical oncologist at Georgetown University and co-chair of ASCO's Living Guidance Committee, sat down with Targeted Oncology to discuss what's new, what's still uncertain, and where the field is headed.

Why Update Now?

Guideline updates don't always happen in response to a single landmark trial or regulatory approval—sometimes, it's simply time to take stock. According to Reuss, that's largely what drove this round.

"Periodically, we do a full guideline update, which is regardless of the extent of a recent burst of data," he explained. "So, we were due for this full guideline update, regardless of where we were at with new approvals and new data."

That said, an update doesn't mean the absence of new information. Even when no single development clears the bar for a formal change in recommendation level, smaller data updates still merit synthesis. As Reuss put it, the committee wanted to "review our current recommendations and where we stand on those," and incorporate data that "maybe [don’t] meet the criteria for a change in level of recommendation, but something we want to put together as a more comprehensive update recommendation."

The Challenge of the Driver Mutation–Negative Guideline

Unlike the driver-positive guideline, where identification of an activating genomic alteration typically points clearly toward a targeted therapy, the driver mutation–negative guideline must account for a broad and heterogeneous patient population. Reuss described the challenge directly: the guideline is divided into sections by histology (nonsquamous vs squamous) and then stratified by PD-L1 expression into 3 tiers: high (≥50%), low (1–49%), and negative (<1%). That structure produces 6 distinct patient subsets, each requiring its own set of recommendations.

"If you do the math, that leads to 6 unique subsets for which we provide guideline updates, where we try to put in data from these trials, many of which were not designed to just look at that 1 subset," Reuss noted. "So, you're looking at subset-level data, subcohort-level data, and trying to make a recommendation, which can be challenging."

One of the more clinically vexing areas remains the PD-L1–negative squamous population. "The committee didn't necessarily feel that one regimen clearly stood above the others," Reuss said. With multiple regimens listed for many of these subsets, the guideline cannot simply point to a single preferred option. Instead, it provides a framework, including a dedicated section on patient-clinician decision-making, that highlights the factors clinicians should weigh for the individual patient in front of them: comorbidities, tolerance for toxicity, time burden of treatment, and more.

Molecular Testing: Now Front and Center

One of the structural changes in this update is perhaps the most foundational: the primacy of comprehensive molecular testing has now been elevated to the top of the driver mutation–negative guideline, mirroring its placement in the driver-positive version. The move reflects a growing recognition that the absence of a driver mutation is itself a clinically meaningful result—and one that must be confirmed before treatment begins.

"The absence of a driver mutation is obviously just as significant, and it's important to wait for that mutation testing results before starting down the path for treatment," Reuss said. "We know there [are] data that even lead to better survival if you give a patient directed treatment."

The urgency is especially acute when immunotherapy is being considered. If a patient starts an immunotherapy-based regimen before molecular results return, and a driver mutation is subsequently identified, switching to a targeted therapy may be complicated or dangerous.

"If you start an immunotherapy-based treatment and then you find one of these driver mutations, we know there's a bulk of data from a lot of different targeted therapies that you could run into significant issues with toxicity," Reuss warned. "So, you really don't want to shoot yourself in the foot from an efficacy, tolerability, or safety standpoint."

For patients who cannot wait—those who are too symptomatic or whose disease is rapidly progressing—Reuss acknowledged a pragmatic exception: "You can always start chemotherapy. You can always give a round of chemotherapy to try to buy patients time while you're waiting for these results."

New Agents in the Subsequent-Line Setting

Antibody-drug conjugates (ADCs)—sometimes called "smart chemotherapies" for their ability to deliver cytotoxic payloads directly to tumor cells—are rapidly reshaping the treatment landscape for NSCLC, and this guideline update reflects that shift.

Trastuzumab deruxtecan (T-DXd; Enhertu), which targets HER2 and carries approval for both HER2-mutated and HER2-overexpressing NSCLC in the subsequent-line setting, was already included in prior guideline iterations. What's new in this update is the addition of telisotuzumab vedotin (Teliso-V; Emrelis), a MET-targeted ADC. The agent received accelerated approval for patients with high MET protein overexpression (defined as 3+ overexpression in at least 50% of tumor cells) based on single-arm data.²

"It is an accelerated approval, based [on] single arm data, so we definitely are awaiting a larger phase 3 randomized study to confirm that," Reuss noted. "But that now is an option that we have."

Importantly, the inclusion of Teliso-V in the driver mutation–negative guideline reinforces the same testing imperative that anchors the rest of the document. MET overexpression is not a classic driver mutation, but it still requires dedicated testing of immunohistochemistry for protein expression to identify eligible patients. "It further reinforces the need for mutation testing and molecular testing," Reuss said.

Open Questions and the Road Ahead

Despite the breadth of available frontline options, a fundamental question persists: which regimen is right for which patient?

"I think it can be very overwhelming to say, well, which regimen is right for my one patient?" Reuss acknowledged. "And I think right now, the short answer is, we don't know."

Several ongoing and recently reported studies are beginning to chip away at that uncertainty. The phase 3 INSIGNA (NCT03793179) study aims to determine whether chemotherapy is truly necessary in patients with high PD-L1 expression. Meanwhile, co-mutations like STK11 and KEAP1, which are associated with immunotherapy resistance, are generating interest as potential biomarkers for more aggressive combination strategies, including dual immune checkpoint blockade with a CTLA-4 inhibitor. Retrospective data from the CheckMate trials and the POSEIDON study (NCT03164616) have suggested potential benefit in those subgroups, but Reuss is cautious: "Adding in these therapies are not without more toxicity. So, it's definitely a challenging guideline."

The recently reported NIPPON study (JCOG2007) from Japan, which compared nivolumab (Opdivo) plus ipilimumab (Yervoy) plus chemotherapy against pembrolizumab (Keytruda) plus chemotherapy in an unselected driver mutation–negative population, offered a cautionary note.

"It was actually a negative study that was stopped early. The added combination immunotherapy led to increased toxicity, which is why the study stopped, and there was really no clear signal of enhanced benefit," Reuss said. He was careful to note this doesn't rule out benefit in molecular subsets, but the prospective data to define those subsets remain elusive.

On the horizon, bispecific antibodies represent another emerging class of agents. Reuss highlighted ivonescimab, which co-targets PD-1 and VEGF, as particularly intriguing. Data primarily from China suggest the molecule outperforms pembrolizumab alone, and seemingly does better than the 2 agents given separately.

"I think the science behind why that is, we need to flush out more, but I think there's potential changes in standard practice in the future if the data we're seeing come out of China continue to hold water in a more global population," he said.

The Bottom Line

The updated ASCO living guideline for stage IV driver mutation–negative NSCLC does not offer a single, simple answer, and Reuss is candid that it can't. What it offers is a rigorously assembled, regularly updated synthesis of evidence, paired with a framework for individualized decision-making.

"We'll never say this is the one regimen you should give," he said. "But what we want to do is provide the information so that clinicians can look at this, put it in the context of the patient sitting in front of them to make an informed decision."

The updated guideline is available at: https://ascopubs.org/doi/10.1200/JCO-25-02825

REFERENCES

1. Reuss J et al. Therapy for Stage IV Non–Small Cell Lung Cancer Without Driver Alterations: ASCO Living Guideline, 2026.3.0. J Clin Oncol 44, e56-e88(2026). DOI:10.1200/JCO-25-02825

2. U.S. FDA approves Emrelis (telisotuzumab vedotin-tllv) for adults with previously treated advanced non-small cell lung cancer (NSCLC) with high c-Met protein overexpression. News release. AbbVie/ May 14, 2025. Accessed March 9, 2026. https://tinyurl.com/yeytkv73