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Table of Contents
Year : 2021  |  Volume : 4  |  Issue : 3  |  Page : 587-588

HER2 alterations in non-small cell lung cancer: More unknowns than knowns!

Department of Medical Oncology, Basavatarakam Indo American Cancer Hospital and RI, Hyderabad, Telangana, India

Date of Submission19-Jul-2021
Date of Decision31-Jul-2021
Date of Acceptance01-Aug-2021
Date of Web Publication10-Sep-2021

Correspondence Address:
Senthil J Rajappa
Basavatarakam Indo American Cancer Hospital and RI, Banjara Hills, Hyderabad - 500 034, Telangana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/crst.crst_168_21

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How to cite this article:
Rajappa SJ. HER2 alterations in non-small cell lung cancer: More unknowns than knowns!. Cancer Res Stat Treat 2021;4:587-8

How to cite this URL:
Rajappa SJ. HER2 alterations in non-small cell lung cancer: More unknowns than knowns!. Cancer Res Stat Treat [serial online] 2021 [cited 2021 Dec 9];4:587-8. Available from: https://www.crstonline.com/text.asp?2021/4/3/587/325899

The article by Bondili et al. titled, “Human epidermal growth factor receptor 2 (HER2) alterations in non-small cell lung cancer (NSCLC)–Druggable or undruggable?”[1] clearly illustrates our limited understanding and ability to target this rare alteration, occurring in 2%–4% of patients with NSCLC. The authors must be commended for painstakingly putting together all the available information about this alteration, right from the basic biology to its clinical implications with reference to prognostic and predictive values. Different types of alterations, including mutations, amplifications, and over expression; different testing methods; and the paucity of large well-conducted clinical trials with heterogeneous populations add to the difficulty of interpreting the data and applying this knowledge to clinical practice.

In contrast to targeting HER2 in breast,[2] gastric,[3] and more recently, endometrial cancers, success has been more elusive in targeting HER2 in NSCLCs. In part, this is due to the lack of clarity regarding the role of HER2 alterations in NSCLCs and the poor understanding of the associations between the various HER2 alterations.[4] The standard paradigm of targeting HER2 amplification and overexpression with antibodies or antibody-drug conjugates and mutations with tyrosine kinase inhibitors has shown inconsistent results.

As discussed in Bondili et al.'s article, the role and place of immune checkpoint inhibitors (ICIs) in HER2-altered NSCLCs is unclear. Although trials on frontline ICIs have excluded patients with alterations in the EGFR and ALK genes, data from the IMMUNOTARGET registry show very limited benefit from single-agent ICIs in patients with HER2 alterations (objective response rate 7% and progression-free survival [PFS] 2.5 months) to recommend this as part of any front-line therapy combination.[5] Adding a potentially toxic and expensive drug to chemotherapy without a clear evidence of benefit, as suggested in the article, may not be rational. Similarly, irrespective of the programmed death-ligand 1 status, there is no evidence of benefit from the use of immunotherapy as a single agent in HER2-amplified or overexpressing NSCLCs.

What is the optimal sequence of therapies in HER2-altered NSCLC? In the absence of any contraindications, standard chemotherapy should be the first-line treatment of choice. Although the impact of HER2 alterations on chemotherapy sensitivity is debatable, there is no consistent evidence to suggest inferior outcomes. The use of any anti-HER2 therapy should be reserved for the second or subsequent lines of treatment. The likely response, PFS, and toxicities with the use of an anti-HER2 drug alone or in combination with other agents should be weighed against the expected results from the standard of care in that clinical setting, whether it is chemotherapy with anti-vascular endothelial growth factor therapy or immunotherapy. The choice of treatment is also likely to be influenced by the access to and affordability of these therapies.[6] Patients with HER2-mutated NSCLCs who can access trastuzumab deruxtecan should use it in the second line, as opposed to patients who can afford only lapatinib or afatinib, in whom it should be used in later lines. This approach however has to be balanced with the deteriorating performance status of the patient, lesser likelihood of responses, and poorer tolerance to therapies in later lines.

With the increasing use of comprehensive genomic profiling using next-generation sequencing, we are likely to come across these “uncommon” alterations more frequently. Currently, there are no Food and Drug Administration-approved therapies for HER2 alterations in NSCLC. This is a clear reflection of our lack of understanding of the impact of the various HER2 and other co-occurring molecular alterations.[7] Our failures are a stark reminder that HER2-mutant NSCLC is an extremely heterogeneous disease; for instance, mutations in the extracellular domain of the HER2 receptor may need to be targeted differently from those in the transmembrane domain. Therefore, the druggability of these mutations will depend on further research to decipher the mechanisms of primary and secondary resistance, which in turn will help in rational drug development and better success.

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Conflicts of interest

There are no conflicts of interest.

  References Top

Bondili SK, NandhanaR, Noronha V, Pawar S, Menon N, Shetty O, et al. HER2 alterations in NSCLC-Druggable or nondruggable. Cancer Res Stat Treat 2021;4:374-84.  Back to cited text no. 1
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Arora S, Gogia A. Recent updates in systemic therapy of breast cancer: A brief narrative review. Cancer Res Stat Treat 2021;4:99-109.  Back to cited text no. 2
  [Full text]  
Simha V, Patil V, Joshi A, Prabhash K, Noronha V. Role of palliative chemotherapy and targeted therapy in advanced esophageal and gastroesophageal junction cancers. Cancer Res Stat Treat 2019;2:172-81.  Back to cited text no. 3
  [Full text]  
Zhao J, Xia Y. Targeting HER2 Alterations in Non–small-cell lung cancer: A comprehensive review. JCO Precision Oncol 2020;4:411-25.  Back to cited text no. 4
Mazieres J, Drilon A, Lusque A, Mhanna L, Cortot AB, Mezquita L, et al. Immune checkpoint inhibitors for patients with advanced lung cancer and oncogenic driver alterations: Results from the IMMUNOTARGET registry. Ann Oncol 2019;30:1321-8.  Back to cited text no. 5
Radhakrishnan V. Drug pricing: A major barrier to access to cancer care in India. Cancer Res Stat Treat 2021;4:195-7.  Back to cited text no. 6
  [Full text]  
Baraibar I, Mezquita L, Gil-Bazo I, Planchard D. Novel drugs targeting EGFR and HER2 exon 20 mutations in metastatic NSCLC. Crit Rev Oncol Hematol 2020;148:102906.  Back to cited text no. 7


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