EGFR Testing for Non-Small Cell Lung Cancer TKI Response

Lab Management Guidelines V1.0.2020 EGFR Testing for Non-Small Cell Lung Cancer TKI Response

MOL.TS.163.A v1.0.2020 Procedures addressed

The inclusion of any procedure code in this table does not imply that the code is under management or requires prior authorization. Refer to the specific Health Plan's procedure code list for management requirements.

Procedure addressed by this guideline Procedure code EGFR Targeted Mutation Analysis 81235

What is EGFR testing in non-small cell lung cancer

Definition

Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, and is associated with exposure to cigarette smoking.1  About 80-85% of NSCLC tumors express the epidermal growth factor receptor (EGFR).1 EGFR is a cell surface receptor that promotes cell growth via activation of its intracellular tyrosine kinase domain when epidermal growth factor binds to its extracellular region. Constitutive activation of the tyrosine kinase domain (via mutation) or overexpression of EGFR results in increased proliferation and survival of cells, leading to the growth of tumors.1  The drugs erlotinib (Tarceva® ), afatinib (Gilotrif® ), and gefitinib (Iressa® ) are used in the treatment of people with advanced NSCLC.1 These drugs are tyrosine kinase inhibitors (TKIs). They directly inhibit the EGFR pathway by binding to the mutated epidermal growth factor receptor and blocking downstream signaling resulting in reduced tumor growth.1,2 o People can develop resistance to erlotinib, afatinib and gefitinib therapy through the development of an EGFR T790M mutation. A third-generation TKI, osimertinib (Tagrisso® ), can be used to treat people who have developed this specific mutation.3  The presence of a mutation in the tyrosine kinase domain of EGFR is associated with positive response to TKIs. About 10-15% of Caucasian and up to 40% of Asian NSCLC patients have these mutations in EGFR. Mutations occur more often in patients with adenocarcinoma, women, and patients who never smoked.1,2,4  Testing an NSCLC patient for EGFR mutations can be helpful to select patients who are more likely to respond to TKI therapy.1

o Patients with activating mutations in exons 18, 19, 20 or 21 of the EGFR gene, which encodes the tyrosine kinase domain of EGFR, are considered good candidates for treatment with erlotinib, afatinib, or gefitinib. Patients found to be wild type are unlikely to respond to erlotinib, afatinib, or gefitinib and there is insufficient evidence at this time to support their use in individuals with other exon mutations. Other treatment options should be considered for these patients.1,5-7 o Patients who develop an EGFR T790M mutation become resistant to treatment with the first- and second-generation TKIs erlotinib, afatinib and gefitinib. This mutation frequently develops after a median of 9 to 13 months of initial TKI therapy and may respond to treatment with the third-generation TKI osimertinib.3,8  EGFR is upstream from another gene, KRAS, in the signaling pathway. Overlapping EGFR mutations and KRAS mutations occur in <1% of patients with lung cancer: patients with NSCLC may have an EGFR mutation or a KRAS mutation, but co- occurrence of both mutations is very rare.1

Test information  Targeted analysis of the EGFR gene can be performed by two different methods:

o Defined mutation panels check specifically for the most common activating mutations in exons 18 to 21 of the EGFR gene. The two most common types of activating EGFR mutations are in-frame deletions in exon 19, and the point mutation, L858R. These mutations account for up to 85% of all EGFR mutations.1 o Sequencing of specific exons (18-21) will find any mutation in the region encoding the tyrosine kinase domain, including deletions in exon 19. The T790M mutation is located on exon 20 and the L858R mutation is located on exon 21.1,8  Testing by either method is sensitive and accurate,1 and both methods are commonly used by commercial laboratories doing testing.  Roche’s cobas EGFR Mutation Test v2 is designed to identify exon 19 deletions

(E19del) or exon 21 (L858R) substitution mutations in the EGFR gene in patients C

with non-small cell lung cancer (NSCLC) eligible for treatment with erlotinib. It is L

also designed to identify the T790M mutation, exon 19 deletions (E19del), or exon C

21 (L858R) substitution mutations in patients eligible for treatment with osimertinib. S This testing is performed on circulating tumor DNA (ctDNA) from a plasma sample 9,10 N

and is commonly known as a liquid biopsy test. -

 Roche’s cobas EGFR Mutation Test v2 had previously been approved for this same R

indication using formalin-fixed paraffin-embedded (FFPE) tissue specimens on F 11

November 13, 2015. G E

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Lab Management Guidelines V1.0.2020

Guidelines and evidence  The National Comprehensive Cancer Network (NCCN, 2019) guidelines state:1

o “Numerous gene alterations have been identified that impact therapy selection. Testing of lung cancer specimens for these alterations is important for identification of potentially efficacious targeted therapies, as well as avoidance of therapies unlikely to provide clinical benefit.” o The EGFR gene is included in the list of gene targets recommended for testing by NCCN.  The National Comprehensive Cancer Network (NCCN, 2019) states the following in regards to liquid biopsy testing for EGFR mutations:1 o “Cell-free/circulating tumor DNA testing should not be used in lieu of a tissue diagnosis.” o "The use of cell-free/circulating tumor DNA testing can be considered in specific clinical circumstances, most notably:

. If a patient is medically unfit for invasive tissue sampling . In the initial diagnostic setting, if following pathologic confirmation of a NSCLC diagnosis there is insufficient material for molecular analysis, cell- free/circulating tumor DNA should be used only if follow-up tissue-based analysis is planned for all patients in which an oncogenic driver is not identified . In patients with a sensitizing EGFR mutation at progression, tissue biopsy."

 The American Society of Clinical Oncology (ASCO, 2018) Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Guideline states that:2 o “The ASCO Expert Panel determined that the recommendations from the CAP/IASLC/AMP molecular testing guideline are clear, thorough, and based upon the most relevant scientific evidence. ASCO endorsed the guideline with minor modifications. Recommendations: This update clarifies that any sample

with adequate cellularity and preservation may be tested and that analytical C

methods must be able to detect mutation in a sample with as little as 20% L cancer cells. It strongly recommends against evaluating epidermal growth factor C receptor (EGFR) expression by immunohistochemistry for selection of patients for EGFR-targeted therapy. ” S N

 The U.S. Food and Drug Administration approved Roche’s cobas EGFR Mutation - 9 Test v2 through their Premarket Approval (PMA) pathway in June 2016: R F o “The U.S. Food and Drug Administration approved cobas EGFR Mutation Test v2 (Roche Molecular Systems, Inc.) using plasma specimens as a companion G

diagnostic test for the detection of exon 19 deletions or exon 21 (L858R) E

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Lab Management Guidelines V1.0.2020

substitution mutations in the epidermal growth factor receptor (EGFR) gene to identify patients with metastatic non-small cell lung cancer (NSCLC) eligible for treatment with Tarceva (erlotinib).” o “Patients who are negative by this test should undergo routine biopsy and testing for EGFR mutations with the FFPE tissue sample type.”  The U.S. Food and Drug Administration approved a label extension of Roche’s cobas EGFR Mutation Test v2 as a companion diagnostic test for osimertinib (Tagrisso®):10 o According to the company, the test can now “be used as a companion diagnostic test (CDx) with Tagrisso for the first line of patients diagnosed with metastatic NSCLC whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 L858R mutations.” The test was previously FDA- approved as a companion diagnostic test for osimertinib for second-line treatment and beyond in NSCLC patients with EGFR T790M mutations.  EGFR is listed as an FDA-approved biomarker for erlotinib, afatinib, gefitinib, and osimertinib.12  Product labeling for erlotinib, afatinib, and gefitinib address EGFR testing. All three products are listed as “first line treatments for patients with metastatic non-small cell lung cancer whose tumors have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 (L858R) substitution mutations as detected by an FDA- approved test.” 5-7  Product labeling for osimertinib notes the product is “a kinase inhibitor indicated for the treatment of patients with metastatic epidermal growth factor receptor (EGFR) T790M mutation-positive non-small cell lung cancer (NSCLC), as detected by an FDA-approved test, whose disease has progressed on or after EGFR TKI therapy.” 8  Osimertinib may also be used as first-line therapy for patients who have mutations in the EGFR gene that sensitize the tumor to earlier-generation tyrosine-kinase inhibitors, or for patients who have the T790M mutation that creates resistance to earlier-generation tyrosine-kinase inhibitors.13 NCCN guidelines indicate that osimertinib is the preferred TKI drug to use when a sensitizing EGFR mutation is detected before first-line systemic therapy is initiated.1 C L

Criteria C EGFR targeted mutation testing is indicated in individuals with metastatic non-small S cell lung cancer prior to initiation of treatment with erlotinib, afatinib, gefitinib, or N - osimertinib therapy. R

For patients whose disease progresses either on or after TKI therapy, repeat EGFR F testing to identify the emergence of a T790M mutation may be considered to determine whether further treatment with osimertinib would be indicated. G E

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Lab Management Guidelines V1.0.2020

Other considerations

Liquid biopsy testing for EGFR targeted mutations will be considered medically necessary for individuals meeting the above criteria and when billed as an individual tumor marker. All other liquid biopsy testing, including panels of genes, is addressed by the guideline Liquid Biopsy Testing - Solid Tumors.

References

1. National Comprehensive Cancer Network: Practice Guidelines in Oncology 1.2019. Non-Small Cell Lung Cancer. Available at http://www.nccn.org/professionals/physician_gls/PDF/nscl.pdf 2. Leighl NB, Rekhtman N, William A. Biermann WA, et al. Molecular Testing for Selection of Patients With Lung Cancer for Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Guideline. J Clin Oncol. 2014;32(32):3673-79. 3. Wang S, Cang S, Liu D. Third-generation inhibitors targeting EGFR T790M mutation in advanced non-small cell lung cancer. J Hematol Oncol. 2016;9(34):1-7. 4. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer-molecular and clinical predictors of outcome. N Eng J Med. 2005;353:133-44. 5. Erlotinib (Tarceva® ) prescribing Information. San Francisco, CA 94080-4990: Genentech Oncology. Available at http://www.gene.com/gene/products/information/pdf/tarceva-prescribing.pdf. Revised April 2010. 6. Gefitinib (Iressa® ) prescribing Information. Wilmington, DE 19850: Astra Zeneca Pharmaceuticals. Available at http://www.azpicentral.com/ires sa/iressa.pdf 7. Afatinib (Gilotrif® ) prescribing information. Ridgefield, CT 06877: Boehringer Ingelheim International GmbH. Available at http://docs.boehringer- ingelheim.com/Prescribing%20Information/PIs/Gilotrif/Gilotrif.pdf. 8. Osimertinib (Tagrisso® ) prescribing information. Wilmington, DE 19850:

AstraZeneca Pharmaceuticals. Available at C

https://www.azpicentral.com/tagrisso/tagrisso.pdf#page=1 L

9. FDA: cobas EGFR Mutation Test v2. September 28, 2016. Available at: C

http://www.accessdata.fda.gov/cdrh_docs/pdf15/P150044A.pdf. S

10. Roche: Roche expands indication for cobas EGFR Mutation Test v2 as a N companion diagnostic with tagrisso. April 2018. Available at - https://molecular.roche.com/news/roche-expands-indication-for-cobas-egfr- R

mutation-test-v2-as-a-companion-diagnostic-with-tagrisso/ F G E

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Lab Management Guidelines V1.0.2020

11. FDA: Summary of Safety and Effectiveness Data for cobas EGFR Mutation Test v2. November 2013. Available at: http://www.accessdata.fda.gov/cdrh_docs/pdf12/P120019S007b.pdf. 12. FDA. Table of valid genomic biomarkers in the context of approved drug labels. Available at http://www.fda.gov/Drugs/ScienceResearch/ResearchAreas/Pharmacogenetics/uc m083378.htm. 13. Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer. N Engl J Med. 2018 Jan 11;378(2):113-125. C L C S N - R F G E

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