Advanced NSCLC Biomarker Testing for KRAS

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Be a precision medicine steward—find KRAS G12C, one of the most prevalent biomarkers in NSCLC¹

Why and who to test

The NSCLC landscape is evolving—check your biomarker panel for actionable biomarkers like KRAS G12C²

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend testing for KRAS G12C in all eligible patients with advanced* NSCLC^3,†,‡
CAP/IASLC/AMP and ASCO Guidelines recommend testing for actionable biomarkers (eg, KRAS G12C) utilizing either a comprehensive panel or targeted testing⁴
Support the ability of all NSCLC patients to obtain and understand their biomarker test results

CAP/IASLC/AMP Guidelines also state that single-gene KRAS testing may be offered in addition to EGFR, ALK, and ROS1, to exclude patients from further testing⁵

Guidelines recognize the value of knowing KRAS G12C status in advanced NSCLC^3-5

*Includes patients with advanced/metastatic NSCLC, but not locally advanced NSCLC.³
^†It is recommended at this time that when feasible, testing be performed via a broad, panel-based approach, most typically performed by NGS.³
^‡The NCCN Guidelines^® for NSCLC provide recommendations for individual biomarkers that should be tested and recommend testing techniques but do not endorse any specific commercially available biomarker assays or commercial laboratories.³

Consider comprehensive genomic profiling at diagnosis to identify actionable biomarkers like KRAS G12C

Conserve tissue

A broad panel uses less tissue than a series of single-gene tests, so additional tests can be run if needed²
Cost-effective

Broad-panel testing can be cost-effective based on the number of biomarkers requiring testing in NSCLC and may avoid the added cost and risk of rebiopsy⁶
Shorter turnaround time

Expanded-panel testing at diagnosis may take less time than consecutive single-gene tests in a process-of-elimination approach⁶
Consistent reporting

Expanded-panel testing provides results for many biomarkers in one report rather than different reports²

KRAS G12C is already included in most NGS panels and can also be detected by currently available PCR and Sanger sequencing methods⁷

Consider testing for KRAS G12C in eligible patients with NSCLC at diagnosis

While the KRAS G12C mutation is most commonly found in smokers, it can occur regardless of clinical or demographic characteristics⁸
Guidelines recommend testing for actionable biomarkers including KRAS G12C in patients with advanced NSCLC²

Percentage of patients receiving
comprehensive (NGS) biomarker testing (2020)⁹

Nearly 1/3 of all patients with advanced or metastatic non-squamous NSCLC in the United States do not receive comprehensive biomarker testing with NGS. Additionally, those with a smoking history and who are racial minorities also have a lower chance of getting tested^9-11

How to test and report

The KRAS G12C point mutation can be detected in tissue and liquid biopsy specimens using common molecular testing methods²

Most NGS platforms already test for KRAS G12C. There are also many PCR platforms capable of KRAS G12C testing⁷

Below is a list of FDA-approved companion diagnostics (CDx) for KRAS G12C for patient identification in NSCLC¹²

Test type	FDA-approved CDx for KRAS G12C patient identification
NGS	Agilent Resolution ctDx FIRST assay (Resolution Bioscience, Inc., liquid) Guardant 360 CDx (Guardant Health, Inc., liquid)
PCR	therascreen KRAS RGQ PCR kit (Qiagen Manchester, Ltd., tissue)

Other FDA-approved tests are available to test for KRAS G12C in NSCLC in addition to CDx tests. Reach out to your preferred reference lab for additional information
CAP/IASLC/AMP Guidelines state that single-gene KRAS testing may be offered in addition to EGFR, ALK, and ROS1 to exclude patients from further testing⁵
- Consider listing KRAS G12C at the variant level in your reports, as some analytical reports may not specify this mutation¹³

Liquid biopsy may be used as an alternative to tissue-based testing¹⁴

Image reproduced with permission from Pantel K, et al.¹⁵

^§The total amount of ctDNA may be <0.01% of the total cfDNA concentration.¹⁵

One form of liquid biopsy consists of obtaining ctDNA from plasma, which can be used to identify genomic alterations¹⁵

Plasma from blood samples contains circulating cfDNA released from healthy cells and tumor cells
Tumor cells release cfDNA known as ctDNA

Liquid biopsy can provide a comprehensive biomarker profile that may inform treatment decisions after 1L NSCLC therapy^16,17

Liquid biopsy may identify actionable mutations like KRAS G12C when tissue quantity is not sufficient¹⁶
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) state that cfDNA testing can be used when a patient is medically unfit for tissue biopsy and/or insufficient tissue is available for molecular analysis³
The CAP/IASLC/AMP guidelines and an IASLC consensus paper support the utility of positive tissue and liquid biopsy results to inform treatment plan decisions^16,18
Because of variable tumor shedding and assay sensitivity, confirming negative liquid biopsy results with tissue biopsy is recommended as mutations cannot be ruled out from a liquid sample alone¹⁶
If tissue biopsy isn't an option for your patient, liquid biopsy may be an alternative^16,18

NSCLC liquid biopsy options exist^19,20

Consensus statement from IASLC recommends liquid biopsy to replace or complement tissue analysis, depending on the clinical scenario¹⁷
Plasma ctDNA may be used for newly diagnosed patients; results are often complementary to tissue analysis¹⁶

Liquid biopsy can enable the identification of actionable biomarkers (such as KRAS G12C) and may inform treatment decisions following 1L NSCLC therapy^16,17

Liquid biopsy allows for detection of biomarkers when tissue is not available¹⁶
In the NILE study, liquid biopsy had a faster median turnaround time of 9 days vs 15 days for tissue biopsy^14,**
Tissue biopsy in NSCLC remains the gold standard^16,17,21
Utilizing cfDNA in addition to tissue increased the number of patients identified to have a driver mutation by 48%,^†† and patients were significantly more likely to receive the complete genotyping that is recommended by guidelines^14,**
If liquid biopsy results are negative, perform a tissue test when feasible as the presence of driver mutations cannot be ruled out from a liquid biopsy sample alone^14,††

**Concordance of PPV for the other guideline-recommended biomarkers was similarly high.¹⁴

^††Among 282 patients with untreated non-squamous mNSCLC, the NILE study (Non-invasive versus Invasive Lung Evaluation) (N=307) enrolled patients at one of 28 North American centers between July 2016 and April 2018. The number of patients identified to have a driver mutation increased from 60 to 89, including those with negative, not assessed for the biomarker identified in cfDNA, or insufficient tissue results. The guideline-recommended biomarkers in this study include: EGFR, ALK, ROS1, BRAF V600E, RET fusions, METex14 skipping, MET amplification, KRAS mutations, and ERBB2 (HER2). The number of patients who received complete genotyping were 268 cfDNA vs 51 tissue (P < 0.0001). Turnaround time was defined as the number of days between test order date and the retrieval of test results.¹⁴

Concordance between ctDNA testing and tissue testing^22,‡‡

If a liquid biopsy returns a positive result, it is actionable. If results are negative for actionable biomarkers, it is recommended to perform a tissue test as the presence of driver mutations cannot be ruled out from a liquid biopsy sample alone^16,18

^‡‡Concordance measured using 109 matched plasma and tissue samples from the Amgen 20170543 study. Samples were evaluated for KRAS G12C-positive or -negative status using the therascreen KRAS RGQ PCR test for tissue and Guardant360 CDx for cfDNA.²²

Comparing Tissue vs Liquid Biopsy NGS Testing

considerations-for-tissue-and-liquid-biopsy-testing

^††Among 282 patients with untreated non-squamous mNSCLC, the NILE study (Non-invasive versus Invasive Lung Evaluation) (N=307) enrolled patients at one of 28 North American centers between July 2016 and April 2018. The number of patients identified to have a driver mutation increased from 60 to 89, including those with negative, not assessed for the biomarker identified in cfDNA, or insufficient tissue results. The guideline-recommended biomarkers in this study include: EGFR, ALK, ROS1, BRAF V600E, RET fusions, METex14 skipping, MET amplification, KRAS mutations, and ERBB2 (HER2). The number of patients who received complete genotyping were 268 cfDNA vs 51 tissue (P < 0.0001). Turnaround time was defined as the number of days between test order date and the retrieval of test results.¹⁴

^§§FDA-approved targeted therapies included EGFR, ALK, ROS1, BRAF V600E, RET, MET exon 14, ERBB2 (HER2), and KRAS^14,16

Reporting and documentation

Considerations that your multidisciplinary team (MDT) may find helpful when reporting biomarker results

Your MDT may include oncologists, pathologists, thoracic surgeons, pulmonologists, and others¹⁸

FOR PATHOLOGISTS

Consider using the upfront summary of your reporting template to document actionable biomarkers^13,27

Pathologist associations offer templates that can guide reporting of actionable biomarkers, like KRAS G12C

Consider uniform and unambiguous nomenclature (ie, KRAS G12C)¹³

Some reports (eg, analytical) may present KRAS G12C results as 12Cys, Gly12Cys (GGT or TGT), or p.G12C^27,28

FOR ONCOLOGISTS

Consider recording patients’ biomarker status in your notes or their chart for ease of future reference²⁹

For KRAS G12C, specifically note G12C to differentiate from other KRAS mutations

FOR ALL MULTIDISCIPLINARY TEAM MEMBERS

Consider using a set location for reports for easy access by all members of the MDT²⁹

A discussion among the MDT may help establish the optimal location and a clear, easily identifiable file naming system
Some reports may be retrieved via fax, email, lab portals, or directly from the EMR

Where to test

FOR ONCOLOGISTS

Check with your current pathologist or lab to confirm KRAS G12C is already included in their panel for NSCLC. However, if testing needs to be sent out, see below for a list of some national reference labs that offer testing for KRAS G12C

Lab/Location	Phone Number/Website
Lab	Location	Website	Phone Number
ARUP LaboratoriesARUP Laboratories Salt Lake City, UT	Salt Lake City, UT	https://www.aruplab.com	(800) 522-2787
https://www.aruplab.com
BioceptBiocept San Diego, CA	San Diego, CA	https://biocept.com	(888) 332-7729
https://biocept.com
BiodesixBiodesix Boulder, CO	Boulder, CO	https://www.biodesix.com	(303) 417-0500
https://www.biodesix.com
Caris Life SciencesCaris Life Sciences Phoenix, AZ	Phoenix, AZ	https://www.carislifesciences.com	(888) 979-8669
https://www.carislifesciences.com
Circulogene TheranosticsCirculogene Theranostics Birmingham, AL	Birmingham, AL	https://circulogene.com	(855) 614-7083
https://circulogene.com
Foundation MedicineFoundation Medicine Cambridge, MA	Cambridge, MA	https://www.foundationmedicine.com	(888) 988-3639
https://www.foundationmedicine.com
GenPath DiagnosticsGenPath Diagnostics Elmwood Park, NJ	Elmwood Park, NJ	https://www.genpathdiagnostics.com	(800) 627-1479
https://www.genpathdiagnostics.com
Guardant HealthGuardant Health Redwood City, CA	Redwood City, CA	https://guardanthealth.com	(855) 698-8887
https://guardanthealth.com
Integrated Oncology / LabCorp Integrated Oncology / LabCorp Phoenix, AZ	Phoenix, AZ	https://oncology.labcorp.com/	AZ: (800) 710-1800 CT/NY: (800) 447-5816 TN: (800) 874-8532
https://oncology.labcorp.com
Mayo Clinic LaboratoriesMayo Clinic Laboratories Rochester, MN	Rochester, MN	https://www.mayocliniclabs.com	(800) 533-1710 or (507) 266-5700
https://www.mayocliniclabs.com
NeoGenomics LaboratoriesNeoGenomics Laboratories Fort Myers, FL	Fort Myers, FL	https://neogenomics.com	(866) 776-5907 (option 3)
https://neogenomics.com
NovogeneNovogene Sacramento, CA	Sacramento, CA	https://en.novogene.com	(916) 252-0068
https://en.novogene.com
Paradigm Cancer DiagnosticsParadigm Cancer Diagnostics Phoenix, AZ	Phoenix, AZ	https://www.paradigmdx.com	(844) 232-4719
https://www.paradigmdx.com
PredicinePredicine Hayward, CA	Hayward, CA	https://www.predicine.com	(650) 300-2188
https://www.predicine.com
Quest DiagnosticsQuest Diagnostics Teterboro, NJ	Teterboro, NJ	https://www.questdiagnostics.com	(866) 697-8378
https://www.questdiagnostics.com
Strata OncologyStrata Oncology Ann Arbor, MI	Ann Arbor, MI	https://www.strataoncology.com	(734) 527-1000
https://www.strataoncology.com
TempusTempus Chicago, IL	Chicago, IL	https://www.tempus.com	(800) 739-4137
https://www.tempus.com
TriCore Reference LaboratoriesTriCore Reference Laboratories Albuquerque, NM	Albuquerque, NM	https://www.tricore.org/home	(505) 938-8888 or (800) 245-3296
https://www.tricore.org/home

The above is a list of facilities with high testing volume that are CLIA certified and accept external samples. CLIA certification was validated using the CDC website, and acceptance of external samples was confirmed by reviewing facility websites and/or contacting facilities directly. Amgen neither recommends nor endorses, and may or may not have financial relationships with, any facility that appears on this list. This list is not intended to be a comprehensive list nor as a referral to any lab listed. If you would like to suggest a facility to be added to this list, please contact Amgen MedInfo at 800-77-AMGEN.

This information is current as of September 9, 2021. Amgen does not guarantee the accuracy of this information, and it is up to the individual healthcare professional to conduct his/her own research.

1L, first line; ALK, anaplastic lymphoma kinase; AMP, Association for Molecular Pathology; ASCO, American Society of Clinical Oncology; BRAF, proto-oncogene B-Raf; CAP, College of American Pathologists; CDC, Centers for Disease Control and Prevention; CDx, companion diagnostic; cfDNA, circulating free DNA; CI, confidence interval; CLIA, Clinical Laboratory Improvement Amendments; CTC, circulating tumor cells; ctDNA, circulating tumor DNA; EGFR, epidermal growth factor receptor; EMR, electronic medical record; ERBB2, erb-B2 receptor tyrosine kinase 2; FFPE, formalin-fixed, paraffin-embedded; GGT, glycine; HER2, human epidermal growth factor receptor 2; IASLC, International Association for the Study of Lung Cancer; IHC, immunohistochemistry; KRAS, Kirsten rat sarcoma; MET, mesenchymal-to-epithelial transition; mNSCLC, metastatic non-small cell lung cancer; n/a, not applicable; NCCN, National Comprehensive Cancer Network; NGS, next-generation sequencing; NSCLC, non-small cell lung cancer; NTRK, neurotrophic tyrosine receptor kinase; PCR, polymerase chain reaction; PD-L1, programmed cell death ligand 1; RET, rearranged during transfection; ROS1, c-ros oncogene 1; TGT, cysteine; TSA, tumor surface area.

Be a precision medicine steward—find KRAS G12C, one of the most prevalent biomarkers in NSCLC¹

Why and who to test

The NSCLC landscape is evolving—check your biomarker panel for actionable biomarkers like KRAS G12C²

Guidelines recognize the value of knowing KRAS G12C status in advanced NSCLC^3-5

Consider comprehensive genomic profiling at diagnosis to identify actionable biomarkers like KRAS G12C

Conserve tissue

Cost-effective

Shorter turnaround time

Consistent reporting