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Immunotherapy Biomarkers

Overview

We’re helping to uncover immunotherapy options for more patients

Cancer immunotherapies have the potential to treat cancer by harnessing the power of our own immune systems; however, not all cancer immunotherapies work for all patients.

A common type of immunotherapy called checkpoint inhibitor therapy typically elicits an overall response rate (ORR) of only 20-40% for patients with solid tumors.1,2,3 The ability to predict who is most likely to respond to cancer immunotherapies could save significant cost and precious time.

The standard of care immunotherapy-related biomarker, programmed death-ligand 1 (PD-L1), may not provide a complete picture of potential candidates for immunotherapy.⁴ We need to look beyond PD-L1 to other clinically relevant genomic signatures that can help stratify patients such as tumor mutational burden (TMB), a quantitative measurement linked to neoantigen expression, and microsatellite instability (MSI) status, which indicates deficient mismatch repair (dMMR).5

Foundation Medicine offers a portfolio of comprehensive genomic profiling tests that can provide TMB, MSI,* and PD-L1 results for your advanced-stage patients.

Help Identify More Eligible Patients

TMB and MSI are important genomic signatures to add to your standard PD-L1 testing because they may help identify more patients for whom immunotherapy could be an option.

All three populations, patients with elevated TMB, high MSI, and positive PD-L1-status, have independently demonstrated improved response rate and prolonged progression-free survival on immunotherapy.7,8,9 However, there are groups of patients that test positive for only one of these three biomarkers.

14% of patients who test negative for PD-L1 by IHC have high MSI or elevated TMB, which may help inform immunotherapy decisions.6

14% of patients who test negative for PD-L1 by IHC have high MSI or elevated TMB, which may help inform immunotherapy decisions

Foundation Medicine Is Your Resource for Cancer Immunotherapy Information

Comprehensive genomic profiling with FoundationOne®CDx, FoundationOne®Liquid, and FoundationOne®Heme can deliver insights into relevant cancer-related genes and measure other genomic signatures and clinical biomarkers, such as TMB, MSI, and PD-L1, that may be associated with immunotherapy.

Our tests can help physicians identify patients who may be more likely to benefit from immunotherapy by providing all relevant genomic signatures from a single vendor.

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Relevant Genomic Signatures

Tumor Mutational Burden (TMB)

TMB is a genomic signature that quantifies the frequency of somatic mutations in a patient’s tumor tissue. Currently FoundationOne CDx and FoundationOne Heme report TMB scores. As TMB is a quantitative genomic signature, current clinical trials are assessing therapeutic response at various cut-off levels in different tumor types.

Elevated TMB correlates with higher neoantigen expression, which helps the immune system recognize tumors.5 It has been detected across numerous tumor types and has been associated with improved response rate and prolonged progression-free survival for patients on immunotherapy.10,11 TMB expands the population of patients who can be considered candidates for immunotherapy beyond standard PD-L1 testing.10,12

Foundation Medicine has established concordance of its comprehensive genomic profiling tests with WES, and has demonstrated clinical utility of TMB to effectively predict immunotherapy response and survival for more than 1,300 patients across 6 separate studies representing 21 different tumor types.5,10,12

Scatter plot showing concordance of Foundation Medicine comprehensive genomic profiling tests with whole exome sequencing.

FoundationOne CDx and FoundationOne Heme provide TMB scores on reports without any additional sample requirements, test requisition form, or cost.

Relevant Genomic Signatures

Microsatellite Instability (MSI)

MSI is a genomic signature that is a signature of deficient mismatch repair (dMMR) which results in an abnormally high frequency of genetic mutations.14 MSI-high status correlates with higher neoantigen expression which helps the immune system recognize tumors. Identification of MSI-high status is part of an FDA-approved indication for pembrolizumab, an immunotherapy drug that has expanded its approval across all solid tumor types in MSI-high patients when previous therapies have failed.15 High MSI levels have been detected in more than 20 types of solid tumors, thus underlining the importance of testing all patients for this key genomic signature.5,16

Foundation Medicine’s hybrid-capture, next-generation sequencing (NGS) methodology has high sensitivity and specificity for clinical MSI-high testing across tumor types.17

Longtail plot showing Microsatellite Instability High prevalence across a variety of cancer types

FoundationOne CDx, FoundationOne Liquid,* and FoundationOne Heme provide MSI status on all reports without any additional tissue, test requisition form, or cost.   

*On FoundationOne Liquid, MSI status will be reported for samples determined to have high microsatellite instability. 

Relevant Genomic Signatures

Programmed Death Ligand-1 (PD-L1)

PD-L1 is a protein biomarker that is strongly associated with immune system suppression.18 Positive PD-L1 immunohistochemistry (IHC) can indicate that a patient will be more likely to respond to immunotherapy. However, the variability of this biomarker highlights the need for additional tools to predict which patients may be candidates for immunotherapy.4 

Beyond PD-L1, TMB and MSI can help you identify and treat more patients eligible for immunotherapy. By combining PD-L1, TMB, and MSI testing, you can be more confident that you are considering all viable treatment options for your patients.

Diagram with overlapping circles showing that there are people who test negative for PD-L1 but are MSI-high or have elevated TMB

PD-L1 is available to order with FoundationOne CDx, FoundationOne Liquid, and FoundationOne Heme on the same test requisition form. PD-L1 testing requires only four additional unstained slides and adds no additional wait time to our standard turnaround time. Scoring and clone utilization for PD-L1 testing is based on FDA-approved indications, learn more here

Download IHC Specimen Instructions

Summary

Biomarker Summary

Foundation Medicine’s portfolio provides reliable and accurate measurements of TMB and MSI by comprehensive genomic profiling and PD-L1 expression by IHC. Leverage our tests to comprehensively help inform immunotherapy treatment options for your patients. 

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Tumor Mutational Burden (TMB)

Definition

TMB is a genomic signature that quantifies the frequency of somatic mutations in a patient’s tumor or in circulating tumor DNA in blood. Increasing TMB correlates with increased numbers of neoantigens, which helps the immune system recognize tumors.

At Foundation Medicine

Reported As

  • Integer score

  • Therapies, trials and content (in the professional services section of Foundation Medicine reports) will be reported using disease- and therapy-specific, score-based cutoffs based on existing clinical data, which may change over time as additional clinical data becomes available.

Microsatellite Instability (MSI)

Definition

MSI is a genomic signature of deficient mismatch repair (dMMR) — which results in an abnormally high frequency of genetic mutations. MSI-high status correlates with higher neoantigen expression, which helps the immune system recognize tumors. 

At Foundation Medicine

 *MSI status will be reported for samples determined to have high microsatellite instability.

Reported As

FoundationOne CDx and 
FoundationOne Heme

  • MSI-High 

  • MSS (microsatellite stable) 

  • CBD (cannot be determined) 

FoundationOne Liquid

  • MSI-High 

  • CBD (cannot be determined) 

Programmed Death Ligand-1 (PD-L1)

Definition

PD-L1 is a protein biomarker whose expression is predictive of response to immunotherapy in multiple tumor types, as demonstrated in numerous clinical trials. 

At Foundation Medicine

*Requires both blood and tissue specimens to proceed with FoundationOne Liquid and PD-L1 testing

Reported As

The type of IHC score is dependent upon tumor type. Scoring and clone utilization is based on FDA-approved indications

  • Tumor proportion score (TPS) 

  • Combined positive score (CPS) 

  • Tumor cell (TC) score (%) 

  • Tumor-infiltrating immune cell (IC) score (%)

References

1. Márquez-Rodas et al. Immune checkpoint inhibitors: therapeutic advances in melanoma. Ann Transl Med. 2015;3(18):267. 

2. Wolchok et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2013;369(2):122-33. 

3. Lipson et al. Antagonists of PD-1and PD-L1 in Cancer Treatment. Seminars in Oncology. 2015;42(4):587-600. 

4. Kerr KM, Hirsch FR. Programmed Death Ligand-1 Immunohistochemistry: Friend Or Foe? Arch Pathol Lab Med. 2016;140:326–31. doi: 10.5858/arpa.2015-0522-SA. 

5. Chalmers ZR, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9:34. doi: 10.1186/s13073-017-0424-2. 

6. Data based on Foundation Medicine experience as of June 2017. 

7. Samstein RM. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nature Genetics 2019;51:202-206. 

8. Stenger M. Pembrolizumab in MSI-H or dMMR Solid Tumors: ‘First Tissue/Site-Agnostic’ Approval by FDA. The ASCO Post [Internet]. 2018 Feb 10 [cited 2019 Jan 2]. Available from: www.ascopost.com/issues/february-10-2018/pembrolizumab-in-msi-h-or-dmmr-solid-tumors-first-tissuesite-agnostic-approval-by-fda/ 

9. Center for Drug Evaluation and Research. (2019, February 06). Approved Drugs - Hematology/Oncology (Cancer) Approvals & Safety Notifications. Retrieved February 07, 2019, from www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm279174.htm   

10. Goodman AM, et al. Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers. Mol Cancer Ther. 2017;16(11):2598-608. doi: 10.1158/1535-7163.MCT-17-0386. 

11. Carbone D, et al. First-line Nivolumab in Stage IV or Recurrent Non-Small-Cell Lung Cancer. N Engl J Med. 2017;376:2415-26. doi: 10.1056/NEJMoa1613493. 

12. Internal Data on File. 

13. Gandara et al. Nat Med. 2018 Sep;24(9):1441-1448. doi: 10.1038/s41591-018-0134-3. Epub 2018 Aug 6. 

14. Kim TM, Laird PW, Park PJ. The Landscape of Microsatellite Instability in Colorectal and Endometrial Cancer Genomes. Cell. 2013;155(4):858-68. doi: 10.1016/j.cell.2013.10.015. 

15. Keytruda (pembrolizumab) [package insert]. Whitehouse Station, NJ: Merck Sharp & Dohme Corp; 2014. 

16. Cortes-Ciriano I, et al. A molecular portrait of microsatellite instability across multiple cancers. Nature commun. 2017;8:15180. 

17. Hall MJ, et al. Evaluation of microsatellite instability (MSI) status 11,573 diverse solid tumors using comprehensive genomic profiling (CGP). Poster session presented at: 2016 ASCO Annual Meeting; 2016 June 3-7; Chicago, IL. 

18. Xu-Monette ZY, et al. PD-1/PD-L1 Blockade: Have We Found the Key to Unleash the Antitumor Immune Response? Front Immunol. 2017;8:1597. doi:10.3389/fimmu.2017.01597. 

FoundationOne CDx is the only FDA-approved in vitro diagnostic test by Foundation Medicine. FoundationOne Liquid and FoundationOne Heme were developed and their performance characteristics determined by Foundation Medicine. They have not been cleared or approved by the U.S. Food and Drug Administration. For more information on our laboratory developed tests (LDTs) please see their respective Technical Specifications at www.foundationmedicine.com.

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Important Safety Information

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FoundationOne CDx

FoundationOne®CDx is a qualitative next-generation sequencing based in vitro diagnostic test for advanced cancer patients with solid tumors and is for prescription use only. The test analyzes 324 genes as well as genomic signatures including microsatellite instability (MSI) and tumor mutational burden (TMB) and is a companion diagnostic to identify patients who may benefit from treatment with specific therapies in accordance with the approved therapeutic product labeling. Additional genomic findings may be reported and are not prescriptive or conclusive for labeled use of any specific therapeutic product. Use of the test does not guarantee a patient will be matched to a treatment. A negative result does not rule out the presence of an alteration. Some patients may require a biopsy. For the complete label, including companion diagnostic indications and important risk information, please visit www.F1CDxLabel.com.