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HER2 mutations (also known as ERBB2 mutations) have emerged as actionable drivers in NSCLC1-3

NSCLC is a heterogeneous disease driven by a wide spectrum of actionable mutations, with HER2 (ERBB2) identified as a driver in 2004.3,4

Currently, HER2 (ERBB2) is identified as an actionable biomarker by the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®).1

Mutations in HER2 (ERBB2) have similar prevalence to other actionable drivers5,6

Graphs showing HER2 alteration includes mutations, amplification, and overexpression. Prevalence of HER2 mutations occurs in 2-4% of patients with non-small cell lung cancer (NSCLC).
Majority of the mutations occur in the TKD at approximately 54%.

In NSCLC, HER2 mutations are unique3

  • HER2 mutations are often mutually exclusive to established oncogenic drivers, such as EGFR and ALK 3
  • ~54% of HER2 mutations occur primarily in the TKD, with the majority located in exon 209
Approximately 89% of HER2 mutations occur primarily in exon 20 vs 10% of EGFR mutations

ALK=anaplastic lymphoma kinase; EGFR=epidermal growth factor receptor; HER2=human epidermal growth factor receptor 2; NCCN=National Comprehensive Cancer Network; NSCLC=non-small cell lung cancer; ROS1=ROS proto-oncogene 1, receptor tyrosine kinase; TKD=tyrosine kinase domain.

Testing for NSCLC mutations is a critical first step in diagnosing HER2-mutated NSCLC1

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NCCN Guidelines® recommend screening for HER2 mutations in all patients with metastatic nonsquamous NSCLC, which includes adenocarcinoma NSCLC1

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NGS-based approaches are best able to detect the broad spectrum of HER2 mutations by utilizing tissue and liquid biopsies1

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Patient selection for testing should not be based on smoking history, gender, or any other clinicopathologic features1

Wait for test results to make a treatment decision11-13:

Targeted treatment after immunotherapy may increase the risk of toxicities in patients with advanced NSCLC who have actionable drivers11-13

NGS=next-generation sequencing

Significant unmet needs remain in the HER2-mutated NSCLC treatment landscape

There is an opportunity to improve outcomes in HER2-mutated NSCLC4,14-16

In patients with HER2-mutated NSCLC:

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50-70% did not respond

50-70% did not respond

to 1L chemotherapy-based treatment4,14

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mPFS was 5.1 months to 8.4 months

mPFS was 5.1 months to 
8.4 months

to 1L chemotherapy-based treatment4,17

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RWE for 1L treatment showed mPFS of 5.3 months and mOS of 14.7 months18*

RWE for 1L treatment showed mPFS of 5.3 months and mOS of 14.7 months18*

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<20% showed response

~80% did not respond

to pan-HER TKIs15,16

*70.5% of patients received chemotherapy-based treatment and 8.2% of patients received TKIs. Included patients with confirmed advanced or metastatic NSCLC between January 1, 2015 and March 31, 2021.18

Unlike other actionable mutations, HER2-mutated NSCLC does not have approved targeted TKI options1

Since HER2 oncogenic driver identification in 2004, 
HER2-mutated NSCLC has had limited treatment variety when compared to other actionable drivers in NSCLC. The toxicities and benefits of chemotherapy have been well characterized, and chemotherapy-based treatment options continue to be part of 1L and 2L recommendations.1,4

Current NCCN Guidelines recommend the following for patients with HER2-mutated NSCLC:

Systemic therapy icon

Systemic therapy1

Systemic therapy1

Platinum-based chemotherapy options with or without immunotherapy†

†Also recommended for patients with advanced NSCLC without actionable drivers.

Antibody drug conjugates (ADCs) icon

Antibody drug conjugates (ADCs)1‡

Antibody drug conjugates (ADCs)1‡

‡mAbs with a cytotoxic chemotherapy payload.

Systemic therapy or best supportive care icon

Systemic therapy or best supportive care1

Systemic therapy or best supportive care1

While the number of therapies targeting other drivers has increased, few options are available for HER2-mutated NSCLC1

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1L=first line; 2L=second line; 3L=third line; mAb=monoclonal antibody; mOS=median overall survival; mPFS=median progression-free survival; RWE=real-world evidence; TKI=tyrosine kinase inhibitor.

Updates are needed in HER2-mutated NSCLC

There has been progress in the last 20 years in NSCLC treatment. However, an unmet need remains for patients with HER2-mutated NSCLC.19

Further research into HER2-mutated NSCLC could expand the understanding of the disease.

References:

  1. Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Non-Small Cell Lung Cancer V1.2024. © National Comprehensive Cancer Network, Inc. 2024. All rights reserved. Accessed January 3, 2024. To view the most recent and complete version of the guidelines, 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.

  2. Zhao J, Xia Y. JCO Precis Oncol. 2020;4:411-425.

  3. Riudavets M, Sullivan I, Abdayem P, Planchard D. ESMO Open. 2021;6(5):100260. doi:10.1016/j.esmoop.2021.100260

  4. Nützinger J, Lee JB, Low JL, et al. Lung Cancer. 2023;186:107385. doi:10.1016/j.lungcan.2023.107385

  5. Chevallier M, Borgeaud M, Addeo A, Friedlaender A. World J Clin Oncol. 2021;12(4):217-237.

  6. Yu X, Ji X, Su C. Front Oncol. 2022;12:860313. doi:10.2289/fonc.2022.860313

  7. Gutierrez C, Schiff R. Arch Pathol Lab Med. 2011;135(1):55-62.

  8. Garrido-Castro AC, Felip E. Transl Lung Cancer Res. 2013;2(2):122-127.

  9. Robichaux JP, Elamin YY, Vijayan RSK, et al. Cancer Cell. 2019;36(4):444-457.e7. doi:10.1016/j.ccell.2019.09.001

  10. Arcila ME, Nafa K, Chaft JE, et al. Mol Cancer Ther. 2013;12(2):220-229. doi:10.1158/1535-7163.MCT-12-0620

  11. Lin JJ, Chin E, Yeap BY, et al. J Thorac Oncol. 2019;14(1):135-140.

  12. Schoenfeld AJ, Arbour KC, Rizvi H, et al. Ann Oncol. 2019;30(5):839-844.

  13. Yamaguchi O, Kaira K, Kawasaki T. Thorac Cancer. 2020;11(4)1045-1051.

  14. Brazel D, Kroening G, Nagasaka M. BioDrugs. 2022;36(6):717-729.

  15. Jebbink M, de Langen AJ, Boelens MC, Monkhorst K, Smit EF. Cancer Treat Rev. 2020;86:101996. doi:10.1016/j.ctrv.2020.101996

  16. Passaro A, Peters S. N Engl J Med. 2022;386(3):286-289.

  17. Wang Y, Zhang S, Wu F, et al. BMC Cancer. 2018;18(1):326. doi:10.1186/s12885-018-4277-x

  18. Baik C, Le X, Lovly CM, et al. Poster presented at 2023 NACLC Annual Meeting; December 1-3, 2023; Chicago, IL.

  19. Imyanitov EN, Iyevleva AG, Levchenko EN. Crit Rev Oncol Hematol. 2021;157:103194. doi:10.1016/j.critrevonc.2020.103194