ERBB2, erb-b2 receptor tyrosine kinase 2; HER2, human epidermal growth factor receptor 2; mNSCLC, metastatic non-small cell lung cancer.

HER2 (ERBB2) MUTATIONS ARE DIFFERENT FROM OTHER HER2 ALTERATIONS IN mNSCLC

3 TYPES OF HER2 ALTERATIONS HAVE BEEN DESCRIBED IN mNSCLC1-4

 HER2 mutations HER2 amplification HER2 overexpression
Alteration
Biology Mutation in the HER2 (ERBB2) gene Abnormally high number of HER2 (ERBB2) gene copies Overabundance of HER2 receptors expressed on the surface of tumor cells
Testing method Primarily via next- generation sequencing (NGS) In situ hybridization (ISH) Immunohistochemistry (IHC)
Relevance in mNSCLC Under investigation Under investigation Under investigation
Relevance in other tumor types Under investigation in other solid tumors Established in breast cancer and gastric cancers Established in breast cancer and gastric cancers; under investigation in various other solid tumors

HER2 mutations in mNSCLC can lead to an aggressive tumor phenotype5

    HER2 mutations change the shape of the HER2 receptor, which triggers hyperactive downstream signaling1,6

  • HER2 signaling promotes uncontrolled cell growth and tumorigenesis

    HER2 mutations can affect the rate of HER2 receptor internalization3,7,8

  • The rate of HER2 receptor internalization is faster when certain mutations exist in the extracellular or kinase domains
  • Investigational agents such as ADCs may rely on the natural mechanism of receptor internalization to release their cytotoxic payload inside the cell7,9

ADC, antibody-drug conjugate.

Learn more about HER2 mutations as a driver of disease in mNSCLC
HER2 MUTATIONS ARE ONCOGENIC DRIVERS THAT CAN AFFECT A PATIENT’S PROGNOSIS IN mNSCLC1,5

INCIDENCE OF HER2 (ERBB2) MUTATIONS IN non-squamous NSCLC

2-4% OF PATIENTS WITH NSCLC HARBOR A HER2 MUTATION1,2,10-12
Pie chart depicting the incidence of HER2 (ERBB2) mutations and other biomarkers in NSCLC
aHER2 (ERBB2) mutations can occur in exon 18-21 of the tyrosine kinase domain, the extracellular and transmembrane regions, and other regions of the gene.

HER2 mutations occur at a similar frequency to other biomarkers such as ROS1 and BRAF
aHER2 (ERBB2) mutations can occur in exon 18-21 of the tyrosine kinase domain, the extracellular and transmembrane regions, and other regions of the gene.
  • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) recommend that targeted therapy for actionable oncogenic drivers take precedence over treatment with an immune checkpoint inhibitor, regardless of PD-L1 expression13
Detected across a range of patient types, HER2 mutations are more common in patients1,2,14-20:
  • With low levels of PD-L1 expression
  • Who do not have another oncogenic driver mutation, such as ALK and EGFR
  • Who are younger, female, and have never smoked
ALK, anaplastic lymphoma kinase; BRAF, v-Raf murine sarcoma viral oncogene homolog B; EGFR, epidermal growth factor receptor; PD-L1, programmed death ligand 1; ROS1, ROS proto-oncogene 1, receptor tyrosine kinase.

HER2 (ERBB2) mutations can impact patient
Outcomes In mNSCLC

Several small studies suggest that patients with HER2-mutant mNSCLC do not respond well to standard therapies18,19,21-23

 ORR mPFS
Chemotherapy 10-18% 4.2-4.9 months
PD-1/PD-L1 inhibitor 14-27% 2.2-3.4 months
mPFS, median progression-free survival; ORR, overall response rate; PD-1, programmed death 1.

HER2 mutations may be associated with a poor prognosis in mNSCLC1,5

mPFS, median progression-free survival; ORR, overall response rate; PD-1, programmed death 1.
THERE IS CONTINUED UNMET NEED FOR PATIENTS WITH HER2-MUTANT mNSCLC5

HER2 (ERBB2) MUTATIONS ARE UNDER ACTIVE CLINICAL INVESTIGATION

NCCN Guidelines® include HER2 mutations as an emerging biomarker, and recommend broad molecular profiling for eligible patients diagnosed with mNSCLC13,24,b

  • Broad molecular profiling, most typically performed by NGS, may help identify eligible patients for clinical trials, such as those with HER2 (ERBB2) mutations

NCCN, National Comprehensive Cancer Network.

bThe NCCN Guidelines® for NSCLC provide recommendations for certain individual biomarkers that should be tested and recommend testing techniques but do not endorse any specific commercially available biomarker assays or commercial laboratories.
Numerous potential approaches are being studied in patients with HER2-mutant mNSCLC, including5:

Antibody-drug conjugates

Immunotherapy combinations

Small molecule inhibitors

REFER TO CLINICAL GUIDELINES, INCLUDING NCCN, FOR FURTHER INFORMATION REGARDING PATIENTS WITH HER2-MUTANT mNSCLC
Explore how to identify HER2 (ERBB2) mutations
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References: 1. Jebbink M, de Langen AJ, Boelens MC, Monkhorst K, Smit EF. The force of HER2 - a druggable target in NSCLC? Cancer Treat Rev. 2020;86:101996. doi:10.1016/j.ctrv.2020.101996 2. Zhao J, Xia Y. Targeting HER2 alterations in non–small-cell lung cancer: a comprehensive review. JCO Precis Oncol. 2020;4:411-425. doi:10.1200/PO.19.00333 3. Oh DY, Bang YJ. HER2-targeted therapies — a role beyond breast cancer. Nat Rev Clin Oncol. 2020;17(1):33-48. doi:10.1038/s41571-019-0268-3 4. Criscitiello C, Morganti S, Curigliano G. Antibody–drug conjugates in solid tumors: a look into novel targets. J Hematol Oncol. 2021;14(1):20. doi:10.1186/s13045-021-01035-z 5. Pillai RN, Behera M, Berry LD, et al. HER2 mutations in lung adenocarcinomas: a report from the Lung Cancer Mutation Consortium.Cancer. 2017;123(21):4099-4105. doi:10.1002/cncr.30869 6. Garrido-Castro AC, Felip E. HER2 driven non-small cell lung cancer (NSCLC): potential therapeutic approaches. Transl Lung Cancer Res. 2013;2(2):122-127. doi:10.3978/j.issn.2218-6751.2013.02.02 7. Li BT, Michelini F, Misale S, et al. HER2-mediated internalization of cytotoxic agents in ERBB2 amplified or mutant lung cancers. Cancer Discov. 2020;10(5):674-687. doi:10.1158/2159-8290.CD-20-0215 8. Arcila ME, Chaft JE, Nafa K, et al. Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin Cancer Res. 2012;18(18):4910-4918. doi:10.1158/1078-0432.CCR-12-0912 9. Leyton JV. Improving receptor-mediated intracellular access and accumulation of antibody therapeutics—the tale of HER2. Antibodies (Basel). 2020;9(3):32. doi:10.3390/antib9030032 10. Jordan EJ, Kim HR, Arcila ME, et al. Prospective comprehensive molecular characterization of lung adenocarcinomas for efficient patient matching to approved and emerging therapies. Cancer Discov. 2017;7(6):596-609. doi:10.1158/2159-8290.CD-16-1337 11. Nassar AH, Adib E, Kwiatkowski DJ. Distribution of KRASG12C somatic mutations across race, sex, and cancer type. N Engl J Med. 2021;384(2):185-187. doi:10.1056/NEJMc2030638 12. Farago AF, Taylor MS, Doebele RC, et al. Clinicopathologic features of non–small-cell lung cancer harboring an NTRK gene fusion. JCO Precis Oncol. 2018;2018:PO.18.00037. doi:10.1200/PO.18.00037 13. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V.1.2022. © National Comprehensive Cancer Network, Inc. 2021. All rights reserved. Accessed December 7, 2021. To view the most recent and complete version of the guideline, go online to NCCN.org. NCCN makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way. 14. Lai WV, Feldman DL, Buonocore DJ, et al. PD-L1 expression, tumor mutation burden and response to immune checkpoint blockade in patients with HER2-mutant lung cancers. Poster presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago, IL. 15. Yoh K, Matsumoto S, Kunimasa K, et al. The efficacy of immune checkpoint inhibitors and PD-L1 status in patients with advanced non-small cell lung cancer harboring oncogenic driver alterations: immuno-oncology biomarker study in LC-SCRUM-Japan. Poster presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago, IL. 16. Tseng JS, Yang TY, Wu CY, et al. Characteristics and predictive value of PD-L1 status in real-world non–small cell lung cancer patients. J Immunother. 2018;41(6):292-299. doi:10.1097/CJI.0000000000000226 17. Mazières J, Drilon A, Lusque A, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: results from the IMMUNOTARGET registry. Ann Oncol. 2019;30(8):1321-1328. doi:10.1093/annonc/mdz167 18. Guisier F, Dubos-Arvis C, Viñas F, et al. Efficacy and safety of anti–PD-1 immunotherapy in patients with advanced NSCLC with BRAF, HER2, or MET mutations or RET translocation: GFPC 01-2018. J Thorac Oncol. 2020;15(4):628-636. doi:10.1016/j.jtho.2019.12.129 19. Dudnik E, Bshara E, Grubstein A, et al. Rare targetable drivers (RTDs) in non-small cell lung cancer (NSCLC): outcomes with immune check-point inhibitors (ICPi). Lung Cancer. 2018;124:117-124. doi:10.1016/j.lungcan.2018.07.044 20. Chen K, Pan G, Cheng G, et al. Immune microenvironment features and efficacy of PD-1/PD-L1 blockade in non-small cell lung cancer patients with EGFR or HER2 exon 20 insertions. Thorac Cancer. 2021;12(2):218-226. doi:10.1111/1759-7714.13748 21. Auliac JB, Dô P, Bayle S, et al. Non-small cell lung cancer patients harboring HER2 mutations: clinical characteristics and management in a real-life setting. Cohort HER2 EXPLORE GFPC 02-14. Adv Ther. 2019;36(8):2161-2166. doi:10.1007/s12325-019-01001-9 22. Wang Y, Zhang S, Wu F, et al. Outcomes of pemetrexed-based chemotherapies in HER2-mutant lung cancers. BMC Cancer. 2018;18(1):326. doi:10.1186/s12885-018-4277-x 23. Xu F, Yang G, Xu H, Yang L, Qiu W, Wang Y. Treatment outcome and clinical characteristics of HER2 mutated advanced non-small cell lung cancer patients in China. Thorac Cancer. 2020;11(3):679-685. doi:10.1111/1759-7714.13317 24. Planchard D, Popat S, Kerr K, et al; ESMO Guidelines Committee. Metastatic non-small cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2018;29(suppl 4):iv192-iv237. doi:10.1093/annonc/mdy275