Do Targeted NGS Panels Include NSCLC Guideline-Recommended Biomarkers?

ABSTRACT

Objectives: National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology recommend the assessment of 12 molecular biomarkers to determine eligibility for targeted drug therapies in metastatic non–small cell lung cancer (mNSCLC). However, variation exists in the composition of next-generation sequencing (NGS) panels. This study evaluates the inclusion of recommended mNSCLC biomarkers in commercially available targeted NGS panels.

Study Design: A descriptive database review was conducted to characterize molecular testing panels.

Methods: Targeted panels were classified as 2 to 50 genes. The DEX Diagnostics Exchange Registry and the Concert Genetic Testing Unit Test Identifier database were searched for NGS-based lung and multicancer indications. Tests were excluded if their indication precluded usage in lung cancer, NGS technology was not used, or the panel was retired. Each panel was assessed for the inclusion of biomarkers from V.11.2024 NCCN guidelines: ALK, BRAF, EGFR, ERBB, KRAS, NTRK1/2/3, RET, ROS1, MET exon 14 skipping, and MET amplification.

Results: Seventy-seven targeted NGS panels were included. The mean number of biomarkers captured in lung-specific vs multicancer panels was similar (6.6 vs 6.4). Most biomarkers were single-nucleotide variants (82%), and the most common were EGFR (91%), KRAS (87%), and BRAF (86%). Fusions and rearrangements were represented in less than half (41%) of panels, and NTRK fusions were often absent, with NTRK1, NTRK2, and NTRK3 appearing in only 23%, 14%, and 19% of the included panels. The inclusion of copy number variant, specifically MET amplification, was rare (12%). Only 5 (6%) panels captured all 12 recommended biomarkers.

Conclusions: Of 77 unique panels evaluated, only 5 captured all recommended biomarkers for mNSCLC. Ensuring targeted panels assess all relevant biomarkers is crucial for optimal patient treatment.

Am J Manag Care. 2026;32(2):In Press

Takeaway Points

The majority of commercially available next-generation sequencing panels with 50 or fewer genes do not include all National Comprehensive Cancer Network guideline–recommended biomarkers in metastatic non–small cell lung cancer (NSCLC), highlighting the following critical issues:

• Resources to help physicians select guideline-compliant panels are limited.
• Ensuring that targeted panels assess all relevant biomarkers is crucial for optimal patient management and health outcomes in NSCLC.
• Payer policies should be adapted to support reimbursement of guideline-compliant panels, including comprehensive molecular diagnostic testing.

L

ung cancer causes the highest number of cancer-related deaths in the US.¹ Significant advancements in the diagnosis and subsequent treatment of metastatic non–small cell lung cancer (mNSCLC) have been realized in the last decade, with improved outcomes achieved through targeted therapies.² A precision medicine paradigm offers a more personalized approach to the treatment of cancer compared with chemotherapy.³ Targeted therapies, when indicated by molecular diagnostic testing, are highly effective when patients are matched to panels with targeted driver mutations.^4,5 However, to optimize clinical outcomes using those therapies, guideline-compliant biomarker testing is needed.⁶

The rapidly evolving biomarker landscape requires laboratory developers to keep test content current with guideline-recommended testing. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology recommend, where feasible, broader molecular profiling that captures genomic variants for FDA-approved therapies and emerging biomarkers, including those biomarkers conferring potential clinical trial eligibility. Ideally, broad molecular profiling identifies all guideline-recommended biomarkers in a single or combination of assays as well as emerging biomarkers.⁷

The V.11.2024 NCCN guidelines for NSCLC specifically recommended the assessment of molecular biomarkers encompassing 3 classes of genetic variation—single-nucleotide variants (SNVs) such as EGFR, BRAF, KRAS, MET, and ERBB2; fusions/rearrangements (F/Rs) including ALK, ROS1, RET, and NTRK1/2/3; and emerging biomarkers including copy number variant (CNV) MET amplification (driver alteration or acquired resistance mechanism)—to determine eligibility for targeted drug therapies.^7,8 As evidence of the rapidly changing biomarker landscape, the V.3.2025 NCCN guidelines were recently updated (January 2025) to include an additional 7 biomarkers, including NRG1 fusion and FGFR1/2/3 fusions and mutations.⁸

In clinical practice, the rates of biomarker testing differ between practice settings and among tumor types and biomarkers, with varying compliance with testing guidelines.⁹ Uptake of biomarker testing remains suboptimal, as highlighted by Sadik et al,⁶ whose work showed that only 50% of patients had testing completed prior to treatment. In a claims-based analysis, at least 44% of patients had inadequate testing.¹⁰ An additional 17% of patients received narrow-panel (< 50 genes) sequencing, potentially limiting access to appropriate targeted therapies.¹⁰ Multigene testing is currently used in clinical practice but could be applied more widely due to its potential to detect additional genomic alterations.¹¹ Next-generation sequencing (NGS) panels have demonstrated superiority over the sequential single-gene testing approach for several reasons, including minimizing tissue insufficiency and higher costs in the latter approach; however, outdated panels may miss treatment- and outcome-altering biomarkers.⁷

Moreover, a panel may be presented as a lung cancer panel but may not include all recommended biomarkers,¹² and variations exist in how payers cover and manage multigene tests.¹¹ Insurer reimbursement is often limited to targeted panels independent of their ability to capture guideline-recommended biomarkers.^12,13

Failure to identify patients eligible for targeted therapies has clinical consequences. In several real-world studies, patients eligible for targeted therapies had superior overall survival when receiving targeted therapies compared with conventional chemotherapy or immunotherapy.^14-16 Scott et al found that patients harboring actionable oncogenic drivers who received concordant care had a 28.8-month median overall survival and that patients eligible for targeted therapy who received nontargeted therapy had a 16.5-month median overall survival.¹⁷ Singal et al found a 7-month survival improvement in mNSCLC when eligible patients received targeted therapy vs a nontargeted alternative (median, 18.6 vs 11.4 months).¹⁵ Bhandari et al found that the adjusted hazard of death was 25% higher in patients who did not receive biomarker-concordant first-line treatment (vs those who did) despite having biomarker-positive disease.¹⁶

Although many insurers limit coverage for NGS tests to panels with 50 or fewer genes, a comprehensive review of the coverage of NSCLC targeted panels of recommended biomarkers has not been reported. The objective of this study was to evaluate the ability of NGS panels for lung cancer with 50 or fewer genes to capture previously recommended biomarkers for mNSCLC across all 3 genomic variant classes.

METHODS

Data Collection and Validation

Our goal was to identify commercially available gene panels that identify mutations in NSCLC to determine subsequent treatment decisions. We searched 2 publicly available databases, the DEX Diagnostics Exchange Registry¹⁸ and the Concert Genetic Testing Unit Test Identifier database (as of 2024),¹⁹ for NGS-based lung cancer and multicancer panels up to July 19, 2024. DEX standardizes molecular diagnostic testing, enabling communication between payers and laboratories. Concert integrates data to streamline test ordering, coverage, and payment. These platforms improve transparency and efficiency in genetic and diagnostic testing.

We filtered tests based on the available methodology for relevant panels focusing on NGS-based lung cancer or multicancer panels (including lung cancer). Key terms for category selection included NSCLC, lung cancer, solid tumors, and NGS. Panels were subsequently excluded if (1) the panel contained a single gene, (2) the panel contained more than 50 genes, (3) the intended indication precluded usage in lung cancer, (4) the test did not use NGS methods, or (5) the panel was no longer commercially available.

We extracted the following data: the title of the panel, the performing laboratory or manufacturer, the laboratory or manufacturer test identifier, the data source (DEX or Concert), and the list of biomarkers included in the panel. Duplicates were identified when the same panel conducted by the same laboratory or manufacturer appeared as a duplicate entry between DEX and Concert databases.

For the qualifying panels, we assessed inclusion of the 12 molecular biomarkers recommended by the V.11.2024 NCCN guidelines.⁷ We selected these guidelines rather than the recently updated NCCN guidelines (January 2025)⁸ because the currently available panels were available during the period in which the V.11.2024 NCCN guidelines were in place. The Table lists V.11.2024 NCCN guideline–
recommended biomarkers for advanced or metastatic NSCLC.

Data Analysis

We assessed panel adequacy by comparing the recommended 12 biomarkers against biomarkers included in each panel by count, class inclusion (SNV, F/R, or CNV) per biomarker, and representation through lung-specific panels vs panels that serve multiple cancers (including lung cancer).

RESULTS

Panel Classification and Data Collection

Overall, 277 NGS-based lung cancer and multicancer panels were identified (Figure 1). We identified 175 results from the 2 DEX searches that were filtered by oncology, including 6 panels by manually selecting NGS panels with 50 or fewer genes. We identified 102 panels through Concert searches, comprising 83 panels of solid tumor profiling tests and 19 lung-specific panels.

Seventy-seven unique targeted panels with 50 or fewer genes from 43 laboratories met the inclusion criteria and were included in the analysis. Fifty-nine (77%) were specific to lung cancer, and 18 (23%) were intended for use in multiple cancers. Seventy percent of panels were from a commercial laboratory, and 30% were from an academic laboratory.

Panel Coverage

The mean numbers of biomarkers captured in lung-specific and multicancer panels were 6.6 and 6.4, respectively, of the recommended 12. The majority of panels (74%) included only 2 classes of variants and fewer than 12 biomarkers (Figure 2), and 75% captured between 3 and 8 of the recommended 12 biomarkers (Figure 3). Twelve panels (16%) included a single class of variants (Figure 2).

Of the panels with all 3 variant classes, 63% captured all 12 biomarkers. Five panels (6%) included all 3 variant classes and all 12 biomarkers, and 3 panels (4%) included 3 classes and fewer than 12 biomarkers (Figure 2).

SNV (82%) was the highest-represented variant class across the 77 included panels, with the most common recommended biomarkers being EGFR (91%), KRAS (87%), and BRAF (86%) (Figure 4). NTRK fusions were most commonly absent in the F/R variant class, with NTRK1, NTRK2, and NTRK3 appearing in only 23%, 14%, and 19% of the included panels, respectively. ALK had a higher percentage of inclusion across panels at 75% among F/R. F/R biomarkers were represented in less than half (41%) of panels. CNV was represented by a single biomarker (MET amplification), with low inclusion across panels at 12%. Sixty-one percent of panels included all 5 recommended SNVs, and only 10% of panels included all 6 F/Rs.

DISCUSSION

We found that the majority (94%) of commercially available targeted NGS panels with 50 or fewer genes did not capture all 12 biomarkers recommended by the V.11.2024 NCCN guidelines for the diagnosis and subsequent treatment of mNSCLC. To our knowledge, this is the first analysis to systematically assess the capture rate of guideline-recommended genomic variants in targeted NGS panels. The ongoing evolution of recommended biomarkers, as evidenced by the NCCN guideline update in January 2025 that added 7 biomarkers,⁸ presents a challenge for NGS panels that are less comprehensive. Importantly, none of the 5 tests that captured the 12 recommended biomarkers in NCCN guidelines V.11.2024 captured all 19 recommended in NCCN guidelines V.3.2025.⁸

The obsolescence of smaller panels is expected in smaller NGS panels as the clinical utility of new genomic variants is established.²⁰ The inadequacy of marketed NGS panels with 50 or fewer genes indicates a need for retirement of noncompliant panels by laboratories or continual panel redesign to ensure panel composition complies with guidelines. The evolving landscape continues to create uncertainty for laboratories and brings new challenges that may further complicate the implementation of comprehensive biomarker testing. Recently, the FDA Laboratory Developed Tests Final Rule (July 2024), which has since been rejected by a federal court, created significant uncertainty in the laboratory industry by grandfathering existing, unmodified tests while requiring FDA approval for any new or modified tests. This requirement would have presented significant barriers to the modification of existing tests.²¹

Available resources to help physicians select guideline-compliant panels are limited. The NCCN guidelines recognize the practical need for NGS-based comprehensive molecular profiling, yet they do not provide guidance supporting test selection or optimal tissue stewardship. In contrast, the American Society of Clinical Oncology (ASCO) strongly recommends that a panel containing more than 50 genes be performed when more than 1 genomic biomarker is associated with an FDA-approved treatment; however, ASCO provides no tools to aid in panel selection.²²

To the best of our knowledge, no electronic health records (EHRs) routinely provide clinical decision support tools to assist in test selection. Furthermore, there is no easy mechanism or centralized resource for providers to assess whether a given panel is guideline compliant. Neither database we used to identify eligible tests contained variant class and gene composition. We searched laboratory websites for this information and needed to contact the laboratories directly for content clarifications in several circumstances. The 5 panels that captured all 3 genomic variant classes and all 12 biomarkers were from academic or regional laboratories. These may not be widely available, may be unknown to ordering physicians, or may not be contracted by insurers outside their respective localities.

Variations in payer coverage policies, prior authorization requirements, and reimbursement for individual tests create ambiguity about who has access to tests and their usage.²³ Large NGS panels are heavily managed through medical policy and through the prior authorization process. NGS panels with fewer than 50 genes are less likely to be managed through a prior authorization process but more likely to give inadequate results. Furthermore, although coverage of a given test for a given tumor by a given payer may be specified in the plan medical policy, no tools exist at the point of care to assist providers. Recognizing these challenges, some payers, including Centene,²⁴ Blue Shield of California,²⁵ Blue Cross Blue Shield of North Carolina,²⁶ and Humana,²⁷ have broad policies allowing NGS-based comprehensive molecular profiling for advanced and metastatic cancers. Other payers, including Aetna^28,29 and UnitedHealthcare,³⁰ target coverage of panels with 50 or fewer genes. Larger panels, which are more likely to include all the relevant markers, are not covered for NSCLC except in panels with a companion diagnostic indication.¹¹

Based on the results of this study, annual certification through an accrediting body or guideline developers could be a valuable approach for ensuring that test composition meets current national guidelines. EHR vendors could create decision support tools presenting disease-specific, guideline-compliant NGS panels to providers at the time of test ordering. Exploring whether reflex testing with panels ordered by a pathologist may increase the likelihood of ordering appropriate testing may also be beneficial.³¹ These data underscore the importance of further investigating whether payers should eliminate noncompliant panels from their coverage and payment policies.

Limitations

The primary limitation of this study is the possibility that we did not identify all commercially available panels with 50 or fewer genes. We utilized 2 publicly available data sets used by US payers to increase the identification of qualifying tests. Given that many US payers, including Medicare, use billing codes generated by DEX and Concert, it is unlikely that widely used tests were missed. A secondary limitation of this study is that our analysis was based on guideline recommendations available at the time of data collection; however, recommendation updates are ongoing and newly released biomarker recommendations are suggested as more evidence becomes available. Our findings are thus likely conservative and provide a compelling argument for the inadequacy of available targeted panels. Future research should assess the relationship between panel coverage and prescribing patterns.

CONCLUSIONS

To date, the vast majority of commercially available NGS panels with 50 or fewer genes has not included all 12 biomarkers recommended by the V.11.2024 NCCN guidelines for mNSCLC. Ensuring that targeted panels assess all relevant biomarkers is crucial for optimal patient management and health outcomes. Payer policies should be adapted to support reimbursement of guideline-compliant panels, including comprehensive molecular diagnostic testing.

Note Regarding NCCN Guidelines

NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Author Affiliations: Curta Inc (JR, EB, DLV), Seattle, WA; Illumina, Inc (SP, JLF), San Diego, CA.

Source of Funding: None.

Author Disclosures: Ms Reynolds, Dr Brouwer, and Dr Veenstra are consultants for Illumina, which manufactures sequencers for both large and small panels discussed in this article. Ms Peng was employed by and holds stock in Illumina. Dr Fox is a full-time employee of Illumina.

Authorship Information: Concept and design (SP, DLV, JLF); acquisition of data (SP, JLF); analysis and interpretation of data (JR, SP, JLF); drafting of the manuscript (JR, SP, EB, DLV, JLF); critical revision of the manuscript for important intellectual content (JR, EB, DLV, JLF); provision of patients or study materials (JLF); obtaining funding (SP); administrative, technical, or logistic support (JR); and supervision (EB, DLV).

Address Correspondence to: Jade Reynolds, BS, Curta Inc, 113 Cherry St, PMB 45802, Seattle, WA 98104-2205. Email: jade.reynolds@curta.com.

REFERENCES

1. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74(1):12-49. doi:10.3322/caac.21820

2. Araghi M, Mannani R, Heidarnejad Maleki A, et al. Recent advances in non-small cell lung cancer targeted therapy; an updated review. Cancer Cell Int. 2023;23(1):162. doi:10.1186/s12935-023-02990-y

3. de Jong D, Das JP, Ma H, et al. Novel targets, novel treatments: the changing landscape of non-small cell lung cancer. Cancers (Basel). 2023;15(10):2855. doi:10.3390/cancers15102855

4. Gazdar AF. Activating and resistance mutations of EGFR in non-small cell lung cancer: role in clinical response to EGFR tyrosine kinase inhibitors. Oncogene. 2009;28(suppl 1):S24-S31. doi:10.1038/onc.2009.198

5. Chan BA, Hughes BG. Targeted therapy for non-small cell lung cancer: current standards and the promise of the future. Transl Lung Cancer Res. 2015;4(1):36-54. doi:10.3978/j.issn.2218-6751.2014.05.01

6. Sadik H, Pritchard D, Keeling DM, et al. Impact of clinical practice gaps on the implementation of personalized medicine in advanced non–small-cell lung cancer. JCO Precis Oncol. 2022;6:e2200246. doi:10.1200/PO.22.00246

7. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 11.2024. Accessed December 1, 2024. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf

8. NCCN. Clinical Practice Guidelines in Oncology. Non-small cell lung cancer, version 3.2025. Accessed February 25, 2025. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf

9. Aitken M, Villa P, Bennet K, Tewary V, Lech C. Optimizing Oncology Care Through Biomarker Adoption: Barriers and Solutions. IQVIA. August 2020. Accessed August 15, 2024. https://www.iqvia.com/-/media/iqvia/pdfs/institute-reports/optimizing-oncology-care-through-biomarker-adoption.pdf

10. Zhang NJ, Kaylor JW, Stockl KM, et al. HSR24-170: utilization of biomarker testing and biomarker-driven targeted therapy among patients with metastatic non–small cell lung cancer. J Natl Compr Canc Netw. 2024;22(2.5):HSR24-170. doi:10.6004/jnccn.2023.7151

11. Lu CY, Loomer S, Ceccarelli R, et al. Insurance coverage policies for pharmacogenomic and multi-gene testing for cancer. J Pers Med. 2018;8(2):19. doi:10.3390/jpm8020019

12. Fox JL. Caveat emptor: a descriptive analysis of guideline-recommended biomarker inclusion in targeted NGS panels for metastatic non-small cell lung cancer (mNSCLC). J Clin Oncol. 2023;41(suppl 16):3124. doi:10.1200/JCO.2023.41.16_suppl.3124

13. Sireci AN, Aggarwal VS, Turk AT, Gindin T, Mansukhani MM, Hsiao SJ. Clinical genomic profiling of a diverse array of oncology specimens at a large academic cancer center: identification of targetable variants and experience with reimbursement. J Mol Diagn. 2017;19(2):277-287. doi:10.1016/j.jmoldx.2016.10.008

14. Aggarwal C, Marmarelis ME, Hwang WT, et al. Association between availability of molecular genotyping results and overall survival in patients with advanced nonsquamous non-small-cell lung cancer. JCO Precis Oncol. 2023;7:e2300191. doi:10.1200/PO.23.00191

15. Singal G, Miller PG, Agarwala V, et al. Association of patient characteristics and tumor genomics with clinical outcomes among patients with non-small cell lung cancer using a clinicogenomic database. JAMA. 2019;321(14):1391-1399. doi:10.1001/jama.2019.3241

16. Bhandari NR, Hess LM, He D, Peterson P. Biomarker testing, treatment, and outcomes in patients with advanced/metastatic non-small cell lung cancer using a real-world database. J Natl Compr Canc Netw. 2023;21(9):934-944.e1. doi:10.6004/jnccn.2023.7039

17. Scott JA, Lennerz J, Johnson ML, et al. Compromised outcomes in stage IV non-small-cell lung cancer with actionable mutations initially treated without tyrosine kinase inhibitors: a retrospective analysis of real-world data. JCO Oncol Pract. 2024;20(1):145-153. doi:10.1200/OP.22.00611

18. Welcome to DEX Diagnostics Exchange. Palmetto GBA. Accessed July 17, 2024. https://www.dexzcodes.com

19. Discover precision health payment accuracy. Concert. Accessed July 17, 2024. https://www.concert.co

20. Malapelle U, Novello S. Biomarker testing in patients with advanced non-small cell lung cancer: the never-ending story. Lancet Reg Health Eur. 2024;38:100845. doi:10.1016/j.lanepe.2024.100845

21. Laboratory developed tests. FDA. Updated October 30, 2024. Accessed November 15, 2024. https://www.fda.gov/medical-devices/in-vitro-diagnostics/laboratory-developed-tests

22. Chakravarty D, Johnson A, Sklar J, et al. Somatic genomic testing in patients with metastatic or advanced cancer: ASCO provisional clinical opinion. J Clin Oncol. 2022;40(11):1231-1258. doi:10.1200/JCO.21.02767

23. Wu AC, Mazor KM, Ceccarelli R, Loomer S, Lu CY. Access to guideline-recommended pharmacogenomic tests for cancer treatments: experience of providers and patients. J Pers Med. 2017;7(4):17. doi:10.3390/jpm7040017

24. Concert Genetics Oncology: circulating tumor DNA and circulating tumor cells for cancer management (liquid biopsy). Centene Corporation. Updated March 1, 2023. Accessed May 1, 2025. https://www.centene.com/content/dam/centene/policies/clinical-policies/CG%20Oncology%20Circulating%20Tumor%20DNA%20Tumor%20Cells%20Liquid%20Biopsy.pdf

25. Oncology: circulating tumor DNA and circulating tumor cells for cancer management (liquid biopsy). Blue Shield of California. June 1, 2023. Accessed May 1, 2025. https://www.blueshieldca.com/content/dam/bsca/en/provider/docs/medical-policies/Oncology-Circulating-Tumor-DNA-Circulating-Tumor-Cells-Liquid-Biopsy.pdf

26. Liquid biopsy AHS-G2054. Blue Cross and Blue Shield of North Carolina. January 2019. Accessed May 1, 2025. https://www.bluecrossnc.com/providers/policies-guidelines-codes/commercial/laboratory/updates/liquid-biopsy

27. Comprehensive genomic profiling and genetic testing for solid tumors. Humana. Updated August 29, 2024. Accessed May 1, 2025. https://assets.humana.com/is/content/humana/Comprehensive_Genomic_Profiling_and_Genetic_Testing_for_Solid_Tumorspdf

28. Aetna: tumor markers. HematoLogics. Updated March 16, 2022. Accessed May 1, 2025. https://www.hematologics.com/wp-content/uploads/2023/05/Aetna-Molecular-Diagnostic-Coverage.pdf

29. Genetic testing. Aetna. Updated April 3, 2025. Accessed May 1, 2025. https://www.aetna.com/cpb/medical/data/100_199/0140.html

30. Molecular oncology testing for solid tumor cancer diagnosis, prognosis, and treatment decisions. UnitedHealthcare. Accessed May 1, 2025. https://www.uhcprovider.com/content/dam/provider/docs/public/policies/comm-medical-drug/molecular-oncology-testing-for-cancer.pdf

31. Smith BF, Hampel KJ, Sidiropoulos N. Benefits of implementing reflex genomic analysis for nonsmall cell lung cancer. J Appl Lab Med. 2024;9(1):28-40. doi:10.1093/jalm/jfad104