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Testing and Targeted Tx for ES NSCLC
Expert Insights Into Testing and Targeted Therapy for Early-Stage NSCLC

Released: June 15, 2026

Jamie E. Chaft
Jamie E. Chaft, MD
Fernando Lopez-Rios
Fernando Lopez-Rios, MD, PhD
Luis Paz-Ares
Luis Paz-Ares, MD, PhD
Soo Ryum (Stewart) Yang
Soo Ryum (Stewart) Yang, MD
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Key Takeaways
  • Comprehensive biomarker testing with broad NGS plus PD-L1 assessment at diagnosis is increasingly considered best practice in early-stage NSCLC, enabling informed treatment selection and supporting enrollment in biomarker-driven clinical trials.
  • Reflex molecular testing at the time of diagnosis can shorten turnaround times and ensure actionable biomarker results are available before multidisciplinary treatment decisions, particularly when neoadjuvant therapy is being considered.
  • Targeted therapies have significantly improved outcomes in biomarker-selected early-stage NSCLC, with agents such as osimertinib, alectinib, and selpercatinib demonstrating substantial improvements in outcomes and supporting the importance of early molecular profiling.

In this commentary, Jamie E. Chaft, MD; Fernando Lopez-Rios, MD, PhD; Luís Paz-Ares, MD, PhD; and Soo Ryum (Stewart) Yang, MD, discuss key considerations for molecular testing and treatment for early-stage non-small-cell lung cancer (NSCLC). 

What is the current landscape of molecular testing and actionable biomarkers for early-stage NSCLC?

Soo Ryum (Stewart) Yang, MD: When we think about early-stage NSCLC, we are talking about stage IB through IIIA and select IIIB disease. Comprehensive biomarker testing should be considered best practice for patients with these stages of NSCLC. Although guidelines from NCCN, ESMO, and IASLC recommend testing for EGFR mutations, ALK fusions, and PD-L1 expression at a minimum, we increasingly recognize the value of broader genomic profiling. A comprehensive next-generation sequencing (NGS) panel combined with PD-L1 testing is often the most tissue-efficient and clinically informative strategy, similar to what we have already learned from metastatic NSCLC. Testing should ideally be performed at diagnosis before systemic therapy decisions are made. 

Luis Paz-Ares, MD: The treatment landscape for early-stage NSCLC has expanded considerably, with evidence supporting immunotherapy in the neoadjuvant, perioperative, and adjuvant settings. Adjuvant trials such as IMpower010 and PEARLS/KEYNOTE-091 demonstrated disease-free survival benefits with atezolizumab and pembrolizumab, reducing the risk of recurrence significantly following surgery and, generally, adjuvant chemotherapy.

Neoadjuvant and perioperative immunotherapy have produced similarly compelling results in this setting. In CheckMate 816 in the neoadjuvant setting, the addition of nivolumab to chemotherapy improved overall survival compared with chemotherapy alone. Perioperative studies with pembrolizumab, nivolumab, and durvalumab have shown significant improvements in event-free survival across resectable stage II-III disease, with the greatest benefit generally observed in patients with higher PD-L1 expression.

For patients with oncogene-driven disease, targeted therapies have transformed outcomes. In EGFR-mutated NSCLC, the ADAURA trial showed that adjuvant osimertinib reduced the risk of recurrence by approximately 75% and demonstrated an overall survival benefit compared with placebo. Similarly, LAURA showed substantial progression-free survival improvements with osimertinib vs placebo after chemoradiation in unresectable stage III disease. In ALK-positive early-stage NSCLC, the ALINA trial showed that adjuvant alectinib reduced recurrence risk by roughly 75%.

Soo Ryum (Stewart) Yang, MD: Looking a little deeper at testing, biomarker test results can tell us what not to recommend for patients with early-stage NSCLC. Of note, if a patient has NSCLC with an EGFR mutation or an ALK fusion, immunotherapy is generally less effective. Conversely, for patients who are negative for EGFR and ALK alterations, neoadjuvant chemoimmunotherapy may be appropriate, and PD-L1 expression can provide useful predictive information regarding potential benefit. We also know that tumors harboring ROS1, RET, NTRK, and ERBB2 alterations share several biologic characteristics with EGFR- and ALK-driven cancers. These tumors appear less likely to benefit from immunotherapy.

Biomarker testing is critical for identifying patients eligible for clinical trials. Numerous studies are evaluating targeted therapies in the neoadjuvant and adjuvant settings for KRAS G12C, RET, ROS1, ERBB2, EGFR exon 20 insertions, and other alterations. Early-stage biomarker testing is a foundation for future progress.

What are some best practices in ensuring timely access to biomarker results?

Soo Ryum (Stewart) Yang, MD: A considerable challenge in managing early-stage NSCLC is ensuring timely access to biomarker results, particularly when neoadjuvant treatment is being considered. Because treatment decisions are often made within a narrow window before surgery, turnaround time is critical. Reflex biomarker testing can significantly improve efficiency by allowing pathologists to initiate molecular testing at the time of diagnosis rather than waiting for requests from treating healthcare professionals (HCPs). Advances in ultra-rapid NGS platforms, as well as selective use of immunohistochemistry and PCR-based testing, can further accelerate the delivery of clinically actionable results.

Fernando Lopez-Rios, MD: Implementing reflex testing is also a cultural shift. Rather than limiting testing to a few currently actionable biomarkers, broad NGS performed upfront for all eligible patients simplifies workflows and may ultimately be more cost-effective. At our institution, NGS is ordered as soon as a primary lung malignancy is diagnosed, even before the final surgical pathology report is completed. This approach has gained broad acceptance among pathologists and has improved access to comprehensive molecular information when treatment decisions need to be made.

Luis Paz-Ares, MD: The value of reflex testing becomes apparent during multidisciplinary discussions. In our practice, NGS and biomarker results are typically available before the patient is first seen by the oncology team, allowing treatment recommendations to be made with complete molecular information in hand. This extends beyond EGFR and ALK; alterations such as RET fusions can influence decisions regarding immunotherapy and future targeted treatment options, making comprehensive testing highly relevant from the outset.

Jamie E. Chaft, MD: There are situations where reflex testing is not possible, particularly when tissue from outside institutions is insufficient for comprehensive analysis. In those cases, rapid communication between oncologists and pathologists is essential, and focused PCR-based testing may provide faster answers for key alterations such as EGFR and ALK while broader profiling is underway.

What are best practices in interpreting molecular testing reports?

Luis Paz-Ares, MD: As biomarker testing becomes more comprehensive, interpretation becomes increasingly challenging. Many HCPs see large NGS reports containing numerous alterations, and it is not always clear which findings are clinically meaningful. That is why I strongly believe molecular tumor boards are essential. Physicians should not be left to interpret complex genomic findings without multidisciplinary input. The conclusions from those discussions should also be documented in the electronic medical record so they remain accessible throughout the patient's treatment journey.

Even in situations where there is not yet an approved targeted therapy, molecular findings can influence clinical decision-making. Access to expert molecular review should be available even for HCPs practicing outside large academic centers.

Fernando Lopez-Rios, MD: The challenge today is no longer simply generating molecular data; it is integrating that information into meaningful clinical recommendations. Molecular tumor boards provide an opportunity for pathologists, molecular biologists, and oncologists to review cases together and ensure that actionable findings are appropriately interpreted. This multidisciplinary approach helps HCPs understand what the results mean and what actions should follow.

Soo Ryum (Stewart) Yang, MD: When reviewing molecular reports, it is important to understand both the genes included in the panel and which findings are clinically actionable. Numerous resources can help prioritize alterations that are relevant for lung cancer treatment decisions and clinical trial enrollment. We also need to integrate molecular findings with pathology information such as PD-L1 expression to arrive at a complete diagnostic understanding.

What are best practices in enrolling patients with early-stage NSCLC in clinical trials?

Jamie E. Chaft, MD: A key principle here is to investigate clinical trial opportunities before administering the first dose of systemic therapy. Some studies require enrollment before treatment begins, and others allow concurrent or sequential approaches. Patients may lose eligibility once treatment has started, so early identification is critical.

I encourage HCPs to actively review available studies through resources such as clinicaltrials.gov and to establish relationships with regional academic centers that may offer biomarker-driven trials. Targeted therapies are extremely promising, but it will take years for many of these studies to mature. Right now, it is our responsibility to enroll patients so that we can answer these important questions and continue advancing the field.

Soo Ryum (Stewart) Yang, MD: Comprehensive biomarker testing is essential not only for identifying approved treatment options but also for identifying patients who may benefit from participation in biomarker-guided clinical trials. These studies have the potential to transform future practice, making broad testing and early trial consideration essential components of precision medicine in early-stage NSCLC.

What are select novel targeted therapy approaches currently being investigated in clinical trials?

Jamie E. Chaft, MD: Despite the tremendous progress we've made with EGFR- and ALK-directed therapies, we still have a significant unmet need. Looking at our institutional experience at Memorial Sloan Kettering, actionable oncogenic drivers can be identified in nearly two thirds of patients with resectable NSCLC. Even after accounting for EGFR and ALK alterations, a large proportion of patients have targetable biomarkers for which we do not yet have approved perioperative therapies.

As such, clinical trials are of critical importance. Notable phase III studies evaluating targeted therapies for early-stage NSCLC include the SUNRAY-02 study of olomorasib (a novel KRAS G12C inhibitor) in KRAS G12C-mutated disease, the Beamion LUNG-3 study of adjuvant zongertinib (a HER2-directed TKI) for HER2-mutated disease, and the TRUST-IV study of adjuvant taletrectinib (a novel ROS1 TKI) for ROS1-positive disease. At the recent ASCO 2026 meeting, the phase III LIBRETTO-432 study demonstrated significantly improved event-free survival with adjuvant selpercatinib vs placebo for patients with early-stage NSCLC. 

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For patients with newly diagnosed stage IB-IIIA NSCLC, what is your preferred approach to molecular testing at diagnosis?

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