Implementing IHC‑based testing in 2L NSCLC

By Laura Boyd

Delayed biomarker results affect over 20% of community‑treated patients, while insufficient tissue is reported in more than 70% of studies, creating persistent barriers to second‑line decision‑making^1-3​

Beyond first‑line (1L) treatment in advanced non–small-cell lung cancer (NSCLC). reliance on baseline genomic testing alone may be insufficient for post-progression decision-making.⁴ Protein‑based immunohistochemistry (IHC) biomarkers are increasingly relevant in later lines; however, real‑world implementation remains inconsistent.⁵ Variability in IHC cut‑offs, assay interpretation, tissue availability, and multidisciplinary (MDT) workflows can delay treatment decisions.² Addressing these gaps is important to ensure patients are appropriately reassessed and considered for approved second-line (2L) treatment options.

Which protein‑based IHC biomarkers are clinically actionable in 2L NSCLC?

Clinically actionable protein‑based IHC biomarkers in 2L NSCLC extend beyond PD‑L1 to include targets such as MET and HER2, where eligibility for approved therapies is defined by IHC expression rather than genomic alteration status.²

However, post‑progression testing practices have not consistently adapted to this shift. Practice variability and documented knowledge gaps contribute to inconsistent identification and use of IHC‑defined therapies in community practice, limiting access to biomarker‑driven treatment options.^6,7

What challenges affect IHC assay selection and result interpretation in community practice?

Challenges affecting IHC assay selection and result interpretation include variability in assay selection driven by differences in assays and platforms, alongside inconsistencies in scoring systems, reporting standards, and validated expression cut-offs.⁵ For newer protein‑based biomarkers, this variability can create uncertainty when determining treatment eligibility, contributing to delays or inconsistent use of approved 2L therapies.^2,8

Where alignment between validated IHC scores and eligibility criteria is unclear, clinicians may hesitate to act on results, particularly in community settings.⁹

How does tissue stewardship influence access to biomarker‑driven 2L treatment options?

Insufficient tissue availability is a common barrier to biomarker reassessment at progression.^2,3 Low tumor cellularity and poor specimen quality can limit comprehensive IHC evaluation, restricting confirmation of eligibility for approved biomarker‑driven therapies. Without optimized biopsy planning, specimen handling, and test prioritization, patients may progress without sufficient material to support informed treatment decisions.^10,11

How can reflex or algorithmic testing workflows support timely 2L decision‑making?

Reflex or algorithmic testing workflows support 2L decision-making by clarifying post-progression testing triggers and coordination between oncology and pathology.¹² Without standardized workflows, biomarker testing after progression is often reactive, contributing to delays between test ordering, result reporting, and treatment selection.³ Reflex or algorithmic testing approaches can support more timely integration of IHC results into 2L clinical decisions.¹²

Which workflow approaches support guideline‑concordant biomarker testing in community settings?

Community‑based evidence associates the following workflow approaches with improved biomarker testing rates:

• Standardized reflex or algorithmic testing protocols
• Defined multidisciplinary communication between oncology and pathology
• Use of tumor boards to coordinate testing and treatment decisions

Collectively, these approaches support more consistent reassessment and alignment with guideline‑concordant care after progression.^3,6

Key takeaways

• MET and HER2, alongside PD-L1, are actionable IHC biomarkers in 2L NSCLC, where eligibility is defined by IHC expression
• Variability in assay selection, scoring, reporting, and cut‑offs can delay eligibility confirmation and 2L treatment selection
• Tissue limitations at progression are common and can restrict access to biomarker‑driven 2L options
• Standardized reflex testing and MDT workflows support timely, guideline‑concordant testing after progression

References

1. Thomas, 2026. Evaluating effective biomarker testing for advanced non–small cell lung cancer in US community oncology practices. https://www.doi.org/10.1200/op-25-01007
2. Fortman, 2026. An evolving landscape: Predictive and therapeutic biomarkers in advanced non-small cell lung cancer. https://www.doi.org/10.3389/fonc.2026.1750153
3. Salazar, 2025. Strategies for improving biomarker testing rates in non-small cell lung cancer in north America: A scoping review. https://www.doi.org/10.21037/jtd-2025-761
4. Wang, 2024. Addressing the unmet need in NSCLC progression with advances in second-line therapeutics. https://www.doi.org/10.37349/etat.2024.00277
5. Aggarwal, 2026. A United States-based real-world study on biomarker testing and rebiopsy rates among patients with non-small cell lung cancer across lines of therapy. https://www.doi.org/10.1016/j.cllc.2025.11.017
6. Monestime, 2025. Identifying barriers and effective strategies to improve biomarker testing rates in non-small cell lung cancer. https://www.doi.org/10.1200/JCO.2025.43.16_suppl.e23226
7. Fox, 2024. The American Cancer Society National Lung Cancer roundtable strategic plan: Advancing comprehensive biomarker testing in non-small cell lung cancer. https://www.doi.org/10.1002/cncr.34628
8. Tsao, 2025. MET (c-Met) protein overexpression is an emerging protein biomarker in non-small cell lung cancer. https://www.doi.org/10.1038/s41698-025-01144-9
9. Serani. 2025. Beyond the genome: Exploring new frontiers in NSCLC management. https://www.onclive.com/view/beyond-the-genome-exploring-new-frontiers-in-lung-cancer-management
10. Steinestel, 2025. Current biomarkers in non-small cell lung cancer – the molecular pathologist's perspective. https://www.doi.org/10.3390/diagnostics15050631
11. Penault-Llorca, 2022. Expert opinion on NSCLC small specimen biomarker testing - Part 1: Tissue collection and management. https://www.doi.org/10.1007/s00428-022-03343-2
12. 2026. Progress and gaps in lung cancer biomarker testing at community centers. https://www.targetedonc.com/view/progress-and-gaps-in-lung-cancer-biomarker-testing-at-community-centers

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