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NSCLC biomarker testing
Precision Management of NSCLC With Biomarker Testing: An APP Perspective

Released: July 13, 2026

Denise Rouse
Denise Rouse, MS, PA-C
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Key Takeaways
  • Broad molecular profiling should be ordered early in eligible patients with advanced or metastatic NSCLC because actionable driver alterations can determine the preferred first-line systemic therapy.
  • PD-L1 expression remains clinically important, but PD-L1 positivity alone should not override pending molecular results and the patient is clinically stable.
  • NPs and PAs can reduce biomarker testing delays by anticipating tissue needs, supporting reflex workflows, tracking results, clarifying liquid biopsy limitations, and translating complex reports into actionable next steps.

In this ClinicalThought commentary, Denise Rouse, MS, PA-C, discusses practical approaches to integrating non-small-cell lung cancer (NSCLC) biomarker testing into routine oncology workflows. The commentary focuses on barriers that NPs and PAs commonly face, including incomplete testing, insufficient tissue, turnaround time, cost concerns, interpretation of complex next-generation sequencing (NGS) reports, and inequitable access to precision oncology.

Why Biomarker Testing Has Become a Frontline Workflow
In the United States, lung cancer remains a major clinical challenge. In 2026, an estimated 229,410 new lung cancer cases and 124,990 deaths are expected, and lung cancer remains the leading cause of cancer death among both men and women. Approximately 85% of lung cancers are NSCLC, and biomarker testing is a routine part of modern NSCLC care rather than a niche step for selected patients.

For NPs and PAs, the diagnosis of lung cancer is just the first step; the next step is finding the information needed to guide the first treatment decision. Compared with the era when most patients received platinum doublet chemotherapy as initial therapy, identifying a driver alteration today can change the treatment conversation, the route of therapy, expected monitoring, adverse event counseling, and whether immunotherapy or targeted therapy is an appropriate treatment option.

This is also why patient education matters. Many patients recognize chemotherapy and immunotherapy from advertisements or from other people they know, but targeted therapy may be unfamiliar. A patient-friendly explanation is that testing may identify the specific change helping the cancer grow, and if that change is actionable, the care team may be able to select a treatment designed to target it.

Germline vs Somatic Testing: Keep the Distinction Clear
Patients often hear the word genetic and immediately worry about their children or other relatives. In NSCLC, most treatment-guiding biomarkers discussed in routine care are somatic alterations, meaning acquired changes in the tumor that are not inherited and are not passed to children. By contrast, germline testing evaluates inherited variants that may have implications for relatives and screening. Making this distinction can reduce anxiety and help patients focus on how biomarker testing may guide their own treatment plan.

What to Test and When
In early-stage NSCLC, molecular biomarker testing should be performed early when perioperative systemic therapy is being considered, particularly in nonsquamous tumors and stage IB-IIIB disease. At minimum, EGFR-sensitizing mutations, ALK alterations, and PD-L1 expression can inform perioperative and adjuvant treatment decisions. In a clinically stable patient, EGFR and ALK molecular test results should be available before starting perioperative immunotherapy, because driver-positive and immunotherapy-based pathways may differ.

In advanced or metastatic NSCLC, broad molecular testing and PD-L1 testing should be ordered early, before first-line systemic therapy selection. Because the list of targetable mutations is rapidly expanding, healthcare professionals should consult updated guidelines from trusted sources like NCCN or ASCO to verify actionable targets.

Among genetic changes, EGFR mutations (exons 18-21) are the most common at 10% to 20%, followed by KRAS G12C at 8% to 15%. ALK fusions fall into a middle group at 3% to 7%. Less frequent changes, which are seen in ≤5%, include MET exon 14 skipping, ERBB2 (HER2) mutations, EGFR exon 20 insertions, ROS1 fusions, BRAF V600E, and RET fusions. The rarest drivers are NRG1 and NTRK fusions, which each occur in less than 1% of cases. Although these are the most common targets, others exist. For instance, uncommon variants like EGFR L861Q can also be targeted with specific therapies.

Liquid biopsy with comprehensive NGS looking for circulating tumor (ct)DNA should be used in addition to tumor tissue. A positive ctDNA result identifies an actionable alteration, but a negative ctDNA result does not reliably exclude one. Tissue testing should be performed concurrently.

Where Testing Breaks Down in Practice
Responses from an advanced practice provider (APP) survey identified that among 39 total respondents, approximately 50% reported routinely using a full NGS panel; some used narrower or “piecemeal testing” strategies to individualize testing based on availability, utility, and cost. That gap matters because sequential single-gene testing can miss biomarkers that may be clinically relevant.

Turnaround time is another recurring barrier. In the aforementioned survey, 39% of respondents identified turnaround time as a major challenge. In practice, patients with stage IV NSCLC may hear that results can take 2-3 weeks and understandably ask why treatment cannot start immediately. The clearest counseling message is that waiting, when clinically safe, may help the team choose the right treatment first rather than starting a regimen that may be suboptimal or is even contraindicated once molecular results return.

Insufficient tissue was identified as the most common barrier. Small biopsies, low-cellularity pleural fluid specimens, or exhausted tissue can delay or prevent complete testing. APPs can help by checking whether tissue is adequate for histology, PD-L1 testing, DNA testing, and RNA fusion testing; asking whether reflex testing has already started; and escalating early when repeat biopsy or plasma testing may be needed.

Interpreting Reports Without Overinterpreting Them
NGS reports can look like another language: letters, numbers, fusions, amplifications, exon calls, and variants of uncertain significance (VUS). The key APP guidance is to confirm the exact alteration, not only the gene name. EGFR amplification is not the same as an EGFR sensitizing mutation. KRAS G12C is not the same as KRAS G12V. A RET fusion is not the same as a RET variant listed as a VUS.

Recent Data Updates From 2026
Recent updates reinforce why broad molecular profiling should be completed early enough to guide first treatment selection in metastatic NSCLC. At the 2026 ASCO Annual Meeting, the 7-year phase III CROWN update showed continued durable benefit in patients who were treated with first-line targeted therapy lorlatinib vs crizotinib in advanced ALK-positive NSCLC. Median progression-free survival remained not reached vs 9.1 months, with 7-year progression-free survival rates of 55% vs 3%. Median time to intracranial progression also remained not reached vs 16.4 months, and no new intracranial progression events were reported after 30 months on lorlatinib. For NPs and PAs, these data reinforce the importance of identifying ALK gene rearrangements before selecting treatment, especially in patients with brain metastases or central nervous system risk concerns.

Other recent first-line targeted therapy updates show why biomarker results should not be treated as later-line details. In EGFR-mutated advanced NSCLC, the phase III FLAURA2 trial showed improved survival with osimertinib plus platinum/pemetrexed chemotherapy vs osimertinib alone, with median overall survival (OS) of 47.5 vs 37.6 months. In the phase III MARIPOSA study, amivantamab plus lazertinib improved outcomes vs osimertinib in previously untreated EGFR exon 19 deletion or exon 21 L858R mutation–positive advanced NSCLC, with final OS analysis showing median OS not estimable vs 36.7 months. These data add nuance to first-line EGFR-directed discussions and underscore the need to identify the exact EGFR alteration before counseling patients.

Recent FDA activity also underscores why HER2/ERBB2 should remain part of advanced nonsquamous NSCLC profiling. Accelerated approvals for HER2/ERBB2-directed therapies in nonsquamous NSCLC with HER2/ERBB2 tyrosine kinase domain activating mutations expand the practical consequences of broad testing. For APP-led oncology workflows, the takeaway is straightforward: complete biomarker testing can change not only whether a patient receives targeted therapy, but which targeted strategy, monitoring plan, and patient education priorities should come next.

Recent data also support the growing relevance of biomarker testing outside the metastatic setting. The phase III LIBRETTO-432 evaluated adjuvant selpercatinib vs placebo in early-stage RET fusion–positive NSCLC and showed improved event-free survival (EFS), with median EFS not reached vs 31.8 months and 2-year EFS of 91.5% vs 61.1% in stage II-IIIA disease. At this time (July 2026), this should be framed as an emerging update rather than routine adjuvant practice unless label and guideline status support its use in that setting.

A Practical Takeaway for the Clinic
For NPs and PAs, NSCLC biomarker testing is not just a report to file in the chart. It is a workflow that starts at diagnosis, protects tissue, tracks pending results, accounts for clinical urgency, and translates molecular information into understandable counseling. If the patient is clinically stable, first-line systemic therapy should generally wait for actionable driver results when those results could change treatment selection. If urgent symptoms require intervention, symptom-directed management or carefully selected bridging strategies may proceed while testing continues.

A practical clinic checklist is helpful: confirm testing was ordered, confirm tissue is adequate, track turnaround time, review whether the report is complete, clarify any VUS or unclear alteration, and make sure the patient understands why the care team may wait before choosing treatment. Those steps help turn biomarker testing from a bottleneck into a path toward individualized care.

Your Thoughts
What part of NSCLC biomarker testing creates the greatest challenge in your practice? Visit the program page to listen to the podcast or download the biomarker testing resource on this topic. Join the discussion and share the workflow questions you most want addressed.

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