Actionable Biomarkers Determined from Broad Molecular Testing for Patients with Stage IV Non-small Cell Lung Cancer (NSCLC) to Inform Targeted Therapy

Description

This measure would calculate the rate of cases where actionable biomarkers for targeted therapy are identified through repeat molecular tests ordered by the provider due to inadequate tissue samples (as determined by the pathologist or receiving physician) for patients with Stage IV NSCLC and established histological subtypes eligible for biomarker testing receiving broad molecular profiling˄ (repeat biopsy and/or plasma testing). Repeat biomarker/molecular test documented by ordering provider in the patient’s electronic medical record.

˄NCCN-Recommended Targets for Molecular Profiling:

EGFR exon 19 deletion or exon 21 L858R mutation positive
NSCL-20 EGFR S768I, L861Q, and/or G719X mutation positive
NSCL-23 EGFR exon 20 insertion mutation positive
NSCL-24 KRAS G12C mutation positive
NSCL-25 ALK rearrangement positive
NSCL-26 ROS1 rearrangement positive
NSCL-29 BRAF V600E mutation positive
NSCL-31 NTRK1/2/3 gene fusion positive
NSCL-32 METex14 skipping mutation positive
NSCL-33 RET rearrangement positive
ERBB2 (HER2) mutation positive
PD-L1 ≥1% and negative for actionable molecular biomarkers above
PD-L1 <1% and negative for actionable molecular biomarkers above

Population

The population includes patients presenting with advanced or metastatic NSCLC disease, having an established histologic subtype of adenocarcinoma, large cell, squamous cell carcinoma, or NSCLC not otherwise specified who are eligible to receive broad molecular profiling (as defined by NCCN guidelines), undergoing repeat molecular testing due to inadequate retrieval of biomarkers through tissue biopsy sampling procedures. Broad molecular profiling˄ approaches to biomarker testing are recommended by NCCN guidelines when feasible to identify all actionable biomarkers. Repeat molecular testing through biopsy and/or plasma testing for all actionable biomarkers (e.g., EGFR, KRAS, ALK, ROS1, BRAF, NTRK1/2/3, MET, RET, and ERBB2 (HER2)) is recommended by NCCN in the absence of sufficient tissue samples during diagnosis, and over the course of a patient’s therapy to examine potential mechanisms of treatment resistance.iv

Biomarker testing, often referred to as molecular or mutation testing, is conducted among patients with a diagnosis of lung cancer to help determine abnormalities in the DNA as well as the presence of specific proteins in a tumor. Broad molecular profiling is recommended to improve treatment decision-making and increase patient access to targeted treatment options specific to the DNA mutation(s) discovered.[1],[2]

NCCN recommends that when feasible, biomarker testing be performed via a broad, panel-based approach defined as molecular testing that identifies all the following biomarkers in either a single assay or combination of a limited number of assays and optimally identifies emerging biomarkers:

˄NCCN-Recommended Targets for Molecular Profiling:

EGFR exon 19 deletion or exon 21 L858R mutation positive
NSCL-20 EGFR S768I, L861Q, and/or G719X mutation positive
NSCL-23 EGFR exon 20 insertion mutation positive
NSCL-24 KRAS G12C mutation positive
NSCL-25 ALK rearrangement positive
NSCL-26 ROS1 rearrangement positive
NSCL-29 BRAF V600E mutation positive
NSCL-31 NTRK1/2/3 gene fusion positive
NSCL-32 METex14 skipping mutation positive
NSCL-33 RET rearrangement positive
ERBB2 (HER2) mutation positive
PD-L1 ≥1% and negative for actionable molecular biomarkers above
PD-L1 <1% and negative for actionable molecular biomarkers above

[1] Riely G. L. (2017). What, When, and How of Biomarker Testing in Non-Small Cell Lung Cancer. Journal of the National Comprehensive Cancer Network : JNCCN, 15(5S), 686–688. https://doi.org/10.6004/jnccn.2017.0073

[2] LUNGEVITY. Biomarker Testing. 2021. Biomarker Tests | LUNGevity Foundation

Place of Care

Clinicians Office

Rationale

Clinicians face significant challenges in obtaining adequate amounts of tissue samples to effectively conduct broad molecular profiling for patients with lung cancer, often resulting in the need for repeat testing.[1],[2] Clinical studies assessing re-biopsy in patients with lung cancer reveal up to 10 – 20% of tissue biopsies are inadequate for molecular testing due to limited retrieval of diagnostic tissue.[3] The National Comprehensive Cancer Network (NCCN) recommends repeat testing through biopsy and/or plasma testing, in the absence of sufficient tissue samples for actionable biomarkers (e.g., EGFR, KRAS, ALK, ROS1, BRAF, NTRK1/2/3, MET, RET, and ERBB2 (HER2)) to guide treatment decision-making aligned with testing results.[4]

There is growing evidence to show the overall effectiveness of implementing plasma testing as an alternative to, or in complement with tissue biopsy for repeat testing, to yield actionable biomarkers for diagnosis, in addition to addressing clinician concern related to patient invasiveness of repeated tissue biopsy.[5],[6] Notably, results from a meta-analysis detecting EGFR mutations in plasma-based testing revealed a similar predictive value (67% sensitivity; 94% specificity) compared to standard tissue biopsy, offering an equally actionable approach to repeat testing that is non-invasive.[7]

Recent advancements in the availability of targeted therapy options for non-small cell lung cancer (NSCLC) achieved by molecular pathology enhancements has led to significant improvements in patient treatment outcomes.[8],[9] Accurately identifying patients eligible to receive these targeted therapies relies heavily on the ability to obtain actionable tissue and/or liquid samples for comprehensive molecular testing. An analysis of commercial and Medicare claims data of over 500,000 patients with NSCLC estimated that for every 1,000 patients, 49.7% were unable to move forward with precision medicine options due to challenges receiving adequate biomarker test results. Further, of those who underwent biomarker testing, an estimated 10.7% were unable to receive targeted treatment options due to insufficient tissue from biopsy.[10] Additional practice gaps impacting a patient’s ability to receive appropriate targeted therapies were noted, including documentation and reporting challenges of test results, variation in provider knowledge of testing options, and low confidence in test value by the ordering provider.

Improved documentation of repeat testing by the clinical care team may address current gaps in tissue sampling procedures (e.g., ensuring targeted treatment initiation based on biomarker results, monitoring how or why repeat testing occurred, documenting the type of test conducted (i.e., tissue biopsy vs. plasma testing)) and help reinforce current practice standards.

[1] Gutierrez, M. E., Choi, K., Lanman, R. B., Licitra, E. J., Skrzypczak, S. M., Pe Benito, R., Wu, T., Arunajadai, S., Kaur, S., Harper, H., Pecora, A. L., Schultz, E. V., & Goldberg, S. L. (2017). Genomic Profiling of Advanced Non-Small Cell Lung Cancer in Community Settings: Gaps and Opportunities. Clinical lung cancer, 18(6), 651–659. https://doi.org/10.1016/j.cllc.2017.04.004

[2] Ferry-Galow KV, Datta V, Makhlouf HR, Wright J, Wood BJ, Levy E, Pisano ED, Tam AL, Lee SI, Mahmood U, Rubinstein LV, Doroshow JH, Chen AP. What Can Be Done to Improve Research Biopsy Quality in Oncology Clinical Trials? J Oncol Pract. 2018 Oct 4;14(11):JOP1800092. doi: 10.1200/JOP.18.00092. Epub ahead of print. PMID: 30285529; PMCID: PMC6237512.

[3] Liam, C. K., Mallawathantri, S., & Fong, K. M. (2020). Is tissue still the issue in detecting molecular alterations in lung cancer?. Respirology (Carlton, Vic.), 25(9), 933–943. https://doi.org/10.1111/resp.13823

[4] National Comprehensive Cancer Network (NCCN). NCCN Guidelines Version 3. 2023 Non-Small Cell Lung Cancer.

[5]Pennell, N. A., Arcila, M. E., Gandara, D. R., & West, H. (2019). Biomarker Testing for Patients With Advanced Non-Small Cell Lung Cancer: Real-World Issues and Tough Choices. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting, 39, 531–542. https://doi.org/10.1200/EDBK_237863

[6] Fox, A. H., Nishino, M., Osarogiagbon, R. U., Rivera, M. P., Rosenthal, L. S., Smith, R. A., Farjah, F., Sholl, L. M., Silvestri, G. A., & Johnson, B. E. (2023). Acquiring tissue for advanced lung cancer diagnosis and comprehensive biomarker testing: A National Lung Cancer Roundtable best-practice guide. CA: a cancer journal for clinicians, 73(4), 358–375. https://doi.org/10.3322/caac.21774

[7] Duffy MJ, O'Byrne K. Tissue and Blood Biomarkers in Lung Cancer: A Review. Adv Clin Chem. 2018;86:1-21. doi: 10.1016/bs.acc.2018.05.001. Epub 2018 May 30. PMID: 30144837.

[8] Araghi M, Mannani R, Heidarnejad Maleki A, Hamidi A, Rostami S, Safa SH, Faramarzi F, Khorasani S, Alimohammadi M, Tahmasebi S, Akhavan-Sigari R. Recent advances in non-small cell lung cancer targeted therapy; an update review. Cancer Cell Int. 2023 Aug 11;23(1):162. doi: 10.1186/s12935-023-02990-y. PMID: 37568193; PMCID: PMC10416536.

[9] Li S, de Camargo Correia GS, Wang J, Manochakian R, Zhao Y, Lou Y. Emerging Targeted Therapies in Advanced Non-Small-Cell Lung Cancer. Cancers (Basel). 2023 May 24;15(11):2899. doi: 10.3390/cancers15112899. PMID: 37296863; PMCID: PMC10251928.

[10] Sadik H, Pritchard D, Keeling DM, Policht F, Riccelli P, Stone G, Finkel K, Schreier J, Munksted S. Impact of Clinical Practice Gaps on the Implementation of Personalized Medicine in Advanced Non-Small-Cell Lung Cancer. JCO Precis Oncol. 2022 Oct;6:e2200246. doi: 10.1200/PO.22.00246. PMID: 36315914; PMCID: PMC9666118.

Comments

The Sadik article [10] cited above estimates that 50% of patients do not receive adequate testing to determine eligibility for targeted treatments. Of patients with European descent, an estimated 55% of patients with metastatic non small cell lung cancer are eligible for targeted therapies [11]. An estimated 55% of 50% of patients not tested or 27.5% of patients receive wrong therapy from lack of testing. Sadik also demonstrated that 1/3 of patients appropriate for targeted therapy did not receive it. So of the 50% of patients tested, 55% are eligible for targeted therapy, yet 1/3 or 9% received wrong therapy from wrong therapy selection.

There is good evidence that wrong therapy results in worse overall survival, ranging from 5.9 months to 18.4 months lost [12-16]. Using an average 12 months of life lost with an estimated 65,000 patients newly diagnosed in the United States [17], an estimated 24,400 patients (36.5%) die prematurely every year from wrong therapy with a similar number of life years lost. This does not include those who received suboptimal diagnostic testing because the panel used did not capture all 12 recommended NCCN biomarkers [18].

Adoption of a national quality metric focused on appropriate testing in non-small cell lung cancer would not only quantify appropriate testing but what also quantify progress towards reducing harms associated with no or inadequate testing. A companion metric assessing whether patients received test-concordant care would further illuminate whether patients received care most likely to improve survival.

Lastly, while non-small cell lung cancer has one of the highest eligibility for targeted therapies, the 100,000 Genomes Project from the UK National Health Service [19] quantifies the frequency of targetable therapies for all cancer types and allows quantification of the harm from suboptimal testing. A non-small cell lung cancer quality diagnostics metric such as the one proposed would serve as a precursor to a broader pan-cancer quality metric and help insure access to the benefits of a precision medicine approach to cancer care.

[11] Adib, E., Nassar, A.H., Abou Alaiwi, S. et al. Genome Med 14, 39 (2022). https://doi.org/10.1186/s13073-022-01041-x

[12] JCO Oncol Pract . 2024 Jan;20(1):145-153. doi: 10.1200/OP.22.00611. Epub 2023 Aug 9.

[13] Al-Ahmadi A, Ardeshir-Larijani F, Fu P, et al. Clin Lung Cancer. 2021;22(1):16-22

[14] Aggarwal C, Marmarelis M, Hwang WT, et al. JCO Precis Oncol. 2023 Jul;7:e2300191

[15] Singal G, Miller PG, Agarwala V, et al. JAMA. 2019;321(14):1391-1399

[16] Bandhari, et al, J Natl Compr Canc Netw 2023;21(9):934–944.e1 doi:10.6004/jnccn.2023.7039

[17] JAMA Oncol. 2021;7(12):1824-1832. doi:10.1001/jamaoncol.2021.4932

[18] Fox, J. J Clin Oncol 41, 2023 (suppl 16; abstr 3124). DOI, 10.1200/JCO.2023.41.16_suppl.3124

[19] Sosinsky, A., Ambrose, J., Cross, W. et al. Nat Med 30, 279–289 (2024). https://doi.org/10.1038/s41591-023-02682-0

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