CEACAM5: A CLUE TO CANCER CELLS

HIDING IN PLAIN SIGHT

Investigating the role of an emerging biomarker Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5)

is currently being explored as a potential biomarker.1 In early

investigational studies, up to 25% of non-squamous (NSQ) non-small

cell lung cancer (NSCLC) patients had evidence of high CEACAM5

expression.2 CEACAM5 has higher differential expression in NSCLC tumor

vs healthy lung tissue.3 Understanding CEACAM5 may potentially give us

a new way to target this malignancy with a poor prognosis.2,4,5

High differential expression in tumors vs healthy cells

CEACAM5 has been shown to have higher expression in NSQ NSCLC and lower expression in healthy lung

tissue.3 This may ultimately allow CEACAM5 to

become a potential target in NSCLC.3

ALK=anaplastic lymphoma kinase; BRAF=v-Raf murine sarcoma viral oncogene homolog B; EGFR=epidermal growth factor receptor; OS=overall survival; PD-L1=programmed death ligand 1; PFS=progression-free survival; ROS1=ROS proto-oncogene 1.

Poor prognosis, limited post-immunotherapy options in NSCLCNSCLC treatment has been transformed by recent advances, and

immunotherapy with or without platinum chemotherapy has increasingly

become the first-line standard of care in the absence of oncogenic driver

alterations.6,7 This has certainly extended survival, but the reality is most

patients will still experience disease progression with immunotherapy.5,7

And when their disease progresses, they have a poor prognosis with

current therapies.8

Innovation is critically needed post-immunotherapy. There are limited sequencing options once resistance

develops to immunotherapy.6,9 Investigating novel targets and biomarkers could possibly help us address

resistance in NSCLC – ideally while also addressing heterogeneity of resistance with current biomarkers

(eg, PD-L1, EGFR, ROS1, BRAF, ALK).9-11

* Real-world outcomes with second-line therapies after failure of first-line immunotherapy or immunotherapy + chemotherapy in advanced NSCLC.8

2.4-5.5 4.6-10.7

Median PFS* Median OS*

CEACAM5

CEACAM5 expression

in NSQ NSCLC

Early investigational studies show CEACAM5 may be highly expressed† in up to 25% of NSQ NSCLC.2 Other

biomarkers currently included in testing panels are

seen less frequently with NSCLC: 1%-5% BRAF, 4%-5%

ALK, 2% ROS1, and (in North America) 9% EGFR.12-15

CEACAM5 high expression2

† Defined as expression at ≥2+ intensity in ≥50% of tumor cell population.2

Up to

25%of

NSQ NSCLC

References: 1. Beauchemin N, Arabzadeh A. Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) in cancer progression and metastasis. Cancer Metastasis Rev. 2013;32(3-4):643-671. 2. Data on file, Sanofi Genzyme; 2021. 3. Decary S, Berne P-F, Nicolazzi C, et al. Clin Cancer Res. 2020;26(24):6589-6599. 4. Hammarström S. The carcinoembryonic antigen (CEA) family: structures, suggested functions and expression in normal and malignant tissues. Semin Cancer Biol. 1999;9(2):67-81. 5. Lazzari C, Bulotta A, Ducceschi M, et al. Historical evolution of second-line therapy in non-small cell lung cancer. Front Med. 2017;4(4):1-8. 6. Hanna NH, Schneider BJ, Temin S, et al. Therapy for stage IV non–small-cell lung cancer without driver alterations: ASCO and OH (CCO) joint guideline update. J Clin Oncol. 2020;38(14):1-25. 7. Pathak R, Pharaon RR, Mohanty A, Villaflor VM, Salgia R, Massarelli E. Acquired resistance to PD-1/PD-L1 blockade in lung cancer: mechanisms and patterns of failure. Cancers. 2020;12(12):3851:1-13. 8. Marmarelis ME, Hwang W-T, Yang Y-X, et al. Real-world outcomes after second-line treatment in non–small cell lung cancer (NSCLC) patients treated with immunotherapy. J Clin Oncol. 2020;38(15 suppl):e21620. 9. Low JL, RJ Walsh, Ang Y, Chan G, Soo RA. The evolving immuno-oncology landscape in advanced lung cancer: first-line treatment of non-small cell lung cancer. Ther Adv Med Oncol. 2019;11:1-22. 10. Fang F, Jin H, Zhou H, et al. Intratumoral heterogeneity as a predictive biomarker in anti-PD-(L)1 therapies for non-small cell lung cancer. Mol Cancer. 2021;20(37):1-6. 11. Lim Z-F, Ma PC. Emerging insights of tumor heterogeneity and drug resistance mechanisms in lung cancer targeted therapy. J Hematol Oncol. 2019;12(134):1-18. 12. O’Leary CG, Andelkovic V, Ladwa R, et al. Targeting BRAF mutations in non-small cell lung cancer. Transl Lung Cancer Res. 2019;8(6):1119-1124. 13. Chia PL, Mitchell P, Dobrovic A, John T. Prevalence and natural history of ALK positive non-small-cell lung cancer and the clinical impact of targeted therapy with ALK inhibitors. Clin Epidemiol. 2014;6:423-432. 14. Bergethon K, Shaw AT, Ou SH, et al. ROS1 rearrangements define a unique molecular class of lung cancers. J Clin Oncol. 2012;30(8):863-870. 15. Graham RP, Treece AL, Lindeman NI, et al. Worldwide frequency of commonly detected EFGR mutations. Arch Pathol Lab Med. 2018;142(2):163-167. 16. Shirasu N, Kuroki M. CEACAM5 (carcinoembryonic antigen-related cell adhesion molecule 5 (carcinoembryonic antigen)). Atlas Genet Cytogenet Oncol Haematol. 2016;20(5):243-249.

=IgV-like domains

= IgC2-like domains stabilized by disulfide bonds

=transmembrane helices

=ending in the lipid bilayer=GPI anchors

=potential glycosylation sites

Adapted from Beauchemin et al. Cancer Metastasis Rev. 2013;32(3-4):643-6711; Hammerström. Semin Cancer Biol. 1999;9(2):67-81.4

Role of this potential target CEACAM5 is a member of the carcinoembryonic antigen (CEA) family of 12 glycoproteins, not to be

confused with the serum CEA tumor marker for colorectal cancer prognosis that was identified years ago.1,4,16

CEACAM5 cell-surface glycoproteins expressed on epithelial tumor cells may play a potential role in tumor

progression, metastasis, and cell adhesion – inhibiting differentiation and apoptosis and disrupting tissue

architecture.1,3

12 glycoproteins of the human CEACAM family1,4

CEACAM1 CEACAM6 CEACAM7 CEACAM16 CEACAM18 CEACAM19 CEACAM20 CEACAM21 CEACAM3 CEACAM4 CEACAM8

Epithelial CEACAMs Other CEACAMs

© 2021 sanofi-aventis U.S. LLC. All rights reserved. MAT-US-2104781-v1.0-06/2021 June 2021

CEACAM5

Detectable via immunohistochemistry CEACAM5 may potentially represent an important advance in detecting cancer cells using tissue-based immunohistochemistry.2,3 Pathologists could assess the

immunochemistry slides to determine the percentage of tumor cells and the intensity

of staining.2 Testing may be performed with new or archival biopsy tissue to inform

treatment planning.2,3

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