Test First, Treat Second: ASCO's Updated Approach to Driver Mutation–Negative NSCLC

In this minisode, we break down the latest update to ASCO's living guideline for stage IV non–small cell lung cancer (NSCLC) without driver mutations — and what it means for clinicians on the front lines of care.

We're drawing on a conversation with Dr. Joshua Reuss, thoracic medical oncologist at Georgetown University and co-chair of ASCO's Living Guidance Committee, who helped explain the key changes, the remaining uncertainties, and where the field is heading.

What changed — and why now? This was a scheduled comprehensive review, not triggered by a single trial or approval. The committee revisited existing recommendations and incorporated emerging data, even when it didn't clear the bar for a formal change in recommendation level.

Why this guideline is especially complex Unlike driver-positive NSCLC, where a mutation points clearly to a targeted therapy, the driver mutation–negative guideline must address a wide, heterogeneous population — split by histology (nonsquamous vs. squamous) and three PD-L1 tiers, resulting in six distinct patient subsets, each with its own evidence base.

Molecular testing moves to the top A key structural change: comprehensive molecular testing is now front and center in the guideline, reinforcing that confirming the absence of a driver mutation is just as critical as finding one. Starting immunotherapy before results return can create serious problems — if a driver mutation surfaces later, switching to targeted therapy may carry significant toxicity risks.

New in the toolkit: Teliso-V Telisotuzumab vedotin (Teliso-V), a MET-targeted antibody-drug conjugate, has been added to the guideline following its accelerated FDA approval for patients with high MET protein overexpression. It joins trastuzumab deruxtecan (T-DXd) in the subsequent-line ADC space — and its inclusion further underscores the need for thorough molecular and protein expression testing.

What we still don't know The honest answer to "which frontline regimen is best for my patient?" is: we don't know yet. Ongoing trials like INSIGNA are tackling whether chemo is necessary in high PD-L1 expressers. Co-mutations like STK11 and KEAP1 are being explored as biomarkers for dual checkpoint blockade strategies, though a recent prospective study (NIPPON) added caution — increased toxicity without a clear efficacy signal.

One to watch: ivonescimab This bispecific antibody co-targeting PD-1 and VEGF is generating buzz, with data from China suggesting it may outperform pembrolizumab alone. Dr. Reuss calls it potentially practice-changing — if the global data hold up.

The takeaway The guideline won't hand you one answer. It's designed to give clinicians the evidence they need to make the best decision for the individual patient in front of them.

🔗 Full guideline: ascopubs.org/doi/10.1200/JCO-25-02825