Appropriate Biomarker/Molecular Testing Based on Available Evidence for Patients with Stage IV Non-small Cell Lung Cancer (NSCLC)

Broad molecular testing, such as next generation sequencing (NGS) has proven to be more effective at identifying actionable biomarkers than traditional single-gene testing (SGT) methods. NGS, has identified almost 40% more gene alterations for which there is an approved targeted therapy, compared to just 26% using SGT.[1]  In a review assessing the clinical impact of NGS testing, researchers found significantly longer progression-free survival and overall survival rates among patients on targeted treatment than those who were not.[2] NGS is a method of sequencing that can be performed on specific groups of genes (called limited variant screening) using panels of varying sizes (1-50 genes, >50 genes, etc.); it is also a method of conducting comprehensive genomic testing (such as whole genome sequencing). 

Clinical guidelines strongly support the incorporation of broad molecular testing into routine practice. The National Comprehensive Cancer Network (NCCN) strongly advises that, when feasible, biomarker testing be performed via a broad, panel-based approach,[3] defined as molecular testing that identifies all the following biomarkers below in either a single assay or combination of a limited number of assays and optimally identifies emerging biomarkers.[4] 

• EGFR exon 19 deletion or exon 21 L858R mutation positive
• EGFR S768I, L861Q, and/or G719X mutation positive
• EGFR exon 20 insertion mutation positive
• KRAS G12C mutation positive
• ALK rearrangement positive
• ROS1 rearrangement positive
• BRAF V600E mutation positive
• NTRK1/2/3 gene fusion positive
• METex14 skipping mutation positive
• RET rearrangement positive
• ERBB2 (HER2) mutation positive
• PD-L1 ≥1% and negative for actionable molecular biomarkers above
• PD-L1 

Additionally, NCCN recommends this broader approach with the "goal of identifying rare driver mutations for which effective drugs may already be available, or to appropriately counsel patients regarding the availability of clinical trials.” Identification of biomarkers supports eligibility screening for enrollment in clinical trials, an approach prioritized by NCCN to ensure access to emerging therapies that could improve survival rates. 

There are significant racial and ethnic disparities in completion of biomarker/molecular testing, which can affect access to clinical trials and initiation of targeted treatment. For instance, Black Americans are less likely than White individuals to receive NGS testing before first-line therapy (36.6% vs. 29.7%, respectively), and less likely to be treated in a clinical trial (3.9% vs. 2.1%, respectively).[5] In another report of patients eligible for EGFR biomarker testing, Asian patients were almost twice as likely to be tested, and Black patients were 25% less likely to be tested, compared to White patients.[6]

Despite evidence to support broad molecular profiling, ordering SGT – and additional testing when SGT results are negative – remains common practice in community oncology settings. SGT may not yield any actionable findings, requiring subsequent testing to identify mutations that could have been initially identified through broader methods. The use of prior SGT significantly increases the turnaround time (TAT) versus broad molecular testing resulting in delays in treatment decisions. In contrast, broad molecular testing alone provides more efficient results. For example, in one study, 71% of patients undergoing broad molecular testing received their test results in less than 2 weeks, compared to only 38% of patients who received broad molecular testing with prior SGT.[7] Additionally, prior negative SGT results are associated with twice as many cancellations of subsequent broad molecular tests for NSCLC due to tissue insufficiency and increased comprehensive genomic profiling DNA extraction failures.[8]

There are multiple practice gaps that impact the capacity for a clinic to initiate targeted treatment for an individual with NSCLC, including appropriate tests not being ordered, treatment started before testing was ordered, and treatment initiated without consideration for test results. Due in part to these factors, as many as 64% of potentially eligible patients with advanced NSCLC are not receiving precision therapy for their condition.[9] In a retrospective study of 7,242 NSCLC patients in community health settings, only 72% received molecular testing, and of that subpopulation, only 14% received comprehensive genomic testing. Molecular testing did increase between 2015-2020, however comprehensive molecular test rates remained low (9-20%) vs. SGT (42-51%).[10] In addition to shortened TAT, the use of broad sequencing can be more cost-effective than SGT. For example, in a five-year model of newly diagnosed NSCLC patients, NGS decreased the expected testing procedure-related costs to the health plan by $24,651, compared to SGT.[11] In terms of cost-savings related to therapy, NGS-directed therapy can result in a cost-effectiveness ratio of $148,786 versus that of SGT-directed therapy. [12] Furthermore, in a hypothetical million-member health plan, not only were test results available 4-6 days faster with NGS versus SGT, but the increase of proportion of patients tested with NGS was associated with significant cost-savings for both CMS and commercial payers.[13]

These findings highlight the need for a quality measure to promote the widespread use of broad molecular testing approaches to reduce disparities in biomarker/molecular testing and patient survival outcomes, as well as to reduce unnecessary testing and improve efficiency in patient management.

[1] Sheffield, B. S., Eaton, K., Emond, B., Lafeuille, M.-H., Hilts, A., Lefebvre, P., Morrison, L., et al. (2023). Cost Savings of Expedited Care with Upfront Next-Generation Sequencing Testing versus Single-Gene Testing among Patients with Metastatic Non-Small Cell Lung Cancer Based on Current Canadian Practices. Current Oncology, 30(2), 2348–2365. MDPI AG. Retrieved from http://dx.doi.org/10.3390/curroncol30020180.

[2] Comprehensive Review on the Clinical Impact of Next-Generation Sequencing Tests for the Management of Advanced Cancer. DOI: 10.1200/PO.22.00715 JCO Precision Oncology no. 7 (2023) e2200715. Published online June 7, 2023.

[3] See “Principles of Molecular and Biomarker Analysis,” page 83 of NCCN NSCLC guidelines. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf

[4] See “Testing Results” in NSCL-19, page 37 of NCCN NSCLC guidelines. https://www.nccn.org/professionals/physician_gls/pdf/nscl.pdf

[5] Bruno, D. S., Hess, L. M., Li, X., Su, E. W., & Patel, M. (2022). Disparities in Biomarker Testing and Clinical Trial Enrollment Among Patients With Lung, Breast, or Colorectal Cancers in the United States. JCO precision oncology, 6, e2100427. https://doi.org/10.1200/PO.21.00427.

[6] Sacchi, E., Li, Y., Miller, V., Curtis, M., (2022). Real-world racial disparities in EGFR testing and third-generation EGFR TKI use among U.S. patients with stage IV NSCLC.  https://ascopubs.org/doi/abs/10.1200/JCO.2022.40.28_suppl.124

[7] Lawrence, L. Comprehensive Genomic Profiling: A Required Tool for Precision Oncology. June 2023. https://dailynews.ascopubs.org/do/comprehensive-genomic-profiling-required-tool-precision-oncology.

[8] Pennell NA, Mutebi A, Zhou Z-Y, et al. Economic Impact of Next-Generation Sequencing Versus Single-Gene Testing to Detect Genomic Alterations in Metastatic Non–Small-Cell Lung Cancer Using a Decision Analytic Model. JCO Precision Oncology. 2019(3):1-9.

[9] Sadik, H., Pritchard, D., Keeling, D. M., Policht, F., Riccelli, P., Stone, G., Finkel, K., Schreier, J., & Munksted, S. (2022). Impact of Clinical Practice Gaps on the Implementation of Personalized Medicine in Advanced Non-Small-Cell Lung Cancer. JCO precision oncology, 6, e2200246. https://doi.org/10.1200/PO.22.00246

[10] Bapat, B., et. al. Actionability of comprehensive genomic profiling (CGP) compared to single-gene and small panels in patients with advanced/metastatic non-small cell lung cancer (aNSCLC): A real-world study. 10.1200/JCO.2022.40.16_suppl.e21114 Journal of Clinical Oncology 40, no. 16_suppl (June 01, 2022) e21114-e21114. 

[11] Yu TM, Morrison C, Gold EJ, et al: Budget impact of next-generation sequencing for molecular assessment of advanced non-small cell lung cancer. Value in Health 21:1278-1285, 2018

[12] Zou, D., Ye, W., Hess, L. M., Bhandari, N. R., Ale-Ali, A., Foster, J., Quon, P., & Harris, M. (2022). Diagnostic Value and Cost-Effectiveness of Next-Generation Sequencing-Based Testing for Treatment of Patients with Advanced/Metastatic Non-Squamous Non-Small-Cell Lung Cancer in the United States. The Journal of molecular diagnostics : JMD, 24(8), 901–914. https://doi.org/10.1016/j.jmoldx.2022.04.010.

[13] Pennell, N. A., Mutebi, A., Zhou, Z. Y., Ricculli, M. L., Tang, W., Wang, H., Guerin, A., Arnhart, T., Dalal, A., Sasane, M., Wu, K. Y., Culver, K. W., & Otterson, G. A. (2019). Economic Impact of Next-Generation Sequencing Versus Single-Gene Testing to Detect Genomic Alterations in Metastatic Non-Small-Cell Lung Cancer Using a Decision Analytic Model. JCO precision oncology, 3, 1–9. https://doi.org/10.1200/PO.18.00356.