HER2 mutations recently joined an expanding list of therapeutically actionable alterations in non-small cell lung cancer (NSCLC). Of note, trastuzumab deruxtecan was recently granted accelerated FDA approval in August 2022 for pre-treated advanced NSCLC tumors harboring an activating HER2 mutation and is the only approved therapy to date for this specific marker.
Various classes of agents including antibody-drug conjugates (ADCs), tyrosine kinase inhibitors (TKIs) and monoclonal antibodies in combination with chemotherapy have been studied in the context of HER2 mutations, overexpression, and amplification. 1,2,3,4,5
Given the rarity and heterogeneity of alterations in HER2, which is commonly used to refer to the protein encoded by the erythroblastic oncogene B (ERBB2), in NSCLC, patient selection for HER2-directed treatment remains a significant clinical challenge.
HER2 mutations in NSCLC were first described almost two decades ago by Stephens et al, who identified mutations in the HER2 kinase domain in 4% of 120 NSCLC tumors and proposed ERBB2 inhibitors should be specifically evaluated in patients with HER2 mutations.6 Thereafter, the oncogenicity of HER2 exon 20 insertion mutations was demonstrated in pre-clinical models, although less is known about uncommon HER2 mutations.7,8
While HER2 mutations, especially insertions in exon 20, appear to be the strongest predictor of response to HER2-directed therapy,5 the significance of HER2 amplification and overexpression is less defined. HER2 amplifications have been found to be mutually exclusive with HER2 mutations in NSCLC,9 whereas the association between HER2 overexpression and mutations/amplifications is controversial.9,10,11,12,13,14
Consequently, clinical trials using various HER2-directed therapies have employed different selection criteria, thereby adding to the complexity of HER2 as a biomarker in NSCLC.1,2,3,4,15,16,17 This underscores the need to refine biomarker selection for HER2-directed therapy, in tandem with implementation of HER2 testing in NSCLC.
As HER2-directed therapies have been approved in breast cancer since 1998, the expanding role of HER2 ADCs has revealed new therapeutic opportunities that could impact the NSCLC treatment landscape. HER2-low expression breast cancer has been described in recent years,17,18 with trastuzumab deruxtecan demonstrating significantly longer progression-free survival compared to physician’s choice of chemotherapy in tumors with HER2 immunohistochemistry (IHC) 1+ or IHC 2+ with a negative in situ hybridization result.20
While the exact mechanism of action remains unknown, it has been hypothesized that these ADCs show a higher bystander killer effect through cleavable linkers and a higher drug-to-antibody ratio, thereby resulting in an enhanced treatment effect even in tumors with low HER2 expression.19,21,22
Similarly, responses to trastuzumab deruxtecan have been observed in NSCLC patients with no detectable HER2 expression or HER2 amplification.1 In parallel, whether this bystander effect can also account for the high incidence of interstitial lung disease observed with trastuzumab deruxtecan in NSCLC warrants closer examination.1
Future directions for HER2 alterations in NSCLC will likely focus on biomarker development, as well as rational sequencing and combination strategies. With the anticipated approval of various HER2-directed therapies in NSCLC, standardization of HER2 testing and its incorporation into routine clinical practice are of paramount importance.22 Poziotinib was notably not granted approval by the FDA’s Oncologic Drugs Advisory Committee for metastatic HER2 exon 20 insertion mutation-positive NSCLC in September 2022, because of concerns about limited responses with short durability, drug toxicities, inadequate dose optimization, and because the confirmatory clinical trial was delayed. As such, ADCs are likely to be favoured in view of higher anti-tumor activity.
DESTINY-Lung04 (NCT05048797) is currently ongoing to evaluate trastuzumab deruxtecan in the first-line setting among advanced HER2-mutated NSCLC, while DESTINY-Lung03 (NCT04686305) aims to assess the safety of trastuzumab deruxtecan in combination with durvalumab and chemotherapy in patients with HER2 overexpression. Safety considerations for combination and sequential approaches will need to be carefully deliberated, particularly in light of the risk of interstitial lung disease.23
In conclusion, HER2 alterations in NSCLC represent a diverse population with unique challenges; the ultimate treatment paradigm will likely be distinct from HER2-driven breast cancer. While further insights will no doubt be gleaned from experiences with other tumour types, it is imperative that clinicians appreciate the intricacies of HER2 testing in NSCLC to optimize patient selection. To that end, upfront next generation sequencing should be encouraged as should enrollment into suitable clinical trials where possible.
References
- 1. Li BT, Smit EF, Goto Y, Nakagawa K, Udagawa H, Mazières J, et al. Trastuzumab Deruxtecan in HER2-Mutant Non–Small-Cell Lung Cancer. N Engl J Med [Internet]. 2021 Sep; Available from: https://doi.org/10.1056/NEJMoa2112431
- 2. Elamin YY, Robichaux JP, Carter BW, Altan M, Gibbons DL, Fossella FV, et al. Poziotinib for Patients With HER2 Exon 20 Mutant Non–Small-Cell Lung Cancer: Results From a Phase II Trial. J Clin Oncol. 2022 Mar 1;40(7):702–9.
- 3. Le X, Cornelissen R, Garassino M, Clarke JM, Tchekmedyian N, Goldman JW, et al. Poziotinib in Non–Small-Cell Lung Cancer Harboring HER2 Exon 20 Insertion Mutations After Prior Therapies: ZENITH20-2 Trial. J Clin Oncol. 2022 Mar 1;40(7):710–8.
- 4.; Mazieres J, Lafitte C, Ricordel C, Greillier L, Negre E, Zalcman G, et al. Combination of Trastuzumab, Pertuzumab, and Docetaxel in Patients With Advanced Non–Small-Cell Lung Cancer Harboring HER2 Mutations: Results From the IFCT-1703 R2D2 Trial. J Clin Oncol. 2022 Mar 1;40(7):719–28.
- 5. Zhao J, Xia Y. Targeting HER2 Alterations in Non–Small-Cell Lung Cancer: A Comprehensive Review. JCO Precis Oncol. 2020 Apr;(4):411–25.
- 6. Stephens P, Hunter C, Bignell G, Edkins S, Davies H, Teague J, et al. Intragenic ERBB2 kinase mutations in tumours. Nature. 2004 Sep 1;431(7008):525–6.
- 7. Shimamura T, Ji H, Minami Y, Thomas RK, Lowell AM, Shah K, et al. Non–Small-Cell Lung Cancer and Ba/F3 Transformed Cells Harboring the ERBB2 G776insV_G/C Mutation Are Sensitive to the Dual-Specific Epidermal Growth Factor Receptor and ERBB2 Inhibitor HKI-272. Cancer Res. 2006 Jul 3;66(13):6487–91.
- 8. Perera Samanthi A., Li Danan, Shimamura Takeshi, Raso Maria G., Ji Hongbin, Chen Liang, et al. HER2YVMA drives rapid development of adenosquamous lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination therapy. Proc Natl Acad Sci. 2009 Jan 13;106(2):474–9.
- 9. Li BT, Ross DS, Aisner DL, Chaft JE, Hsu M, Kako SL, et al. HER2 Amplification and HER2 Mutation Are Distinct Molecular Targets in Lung Cancers. J Thorac Oncol. 2016 Mar 1;11(3):414–9.
- 10. Arcila ME, Chaft JE, Nafa K, Roy-Chowdhuri S, Lau C, Zaidinski M, et al. Prevalence, clinicopathologic associations, and molecular spectrum of ERBB2 (HER2) tyrosine kinase mutations in lung adenocarcinomas. Clin Cancer Res Off J Am Assoc Cancer Res. 2012/07/03 ed. 2012 Sep 15;18(18):4910–8.
- 11. Hirsch FR, Varella-Garcia M, Franklin WA, Veve R, Chen L, Helfrich B, et al. Evaluation of HER-2/neu gene amplification and protein expression in non-small cell lung carcinomas. Br J Cancer. 2002;86(9):1449–56.
- 12. Suzuki M, Shiraishi K, Yoshida A, Shimada Y, Suzuki K, Asamura H, et al. HER2 gene mutations in non-small cell lung carcinomas: Concurrence with her2 gene amplification and her2 protein expression and phosphorylation. Lung Cancer. 2015 Jan 1;87(1):14–22.
- 13. Nakamura H, Saji H, Ogata A, Hosaka M, Hagiwara M, Kawasaki N, et al. Correlation between encoded protein overexpression and copy number of the HER2 gene with survival in non-small cell lung cancer. Int J Cancer. 2003 Jan;103(1):61–6.
- 14. Tan AC, Saw SPL, Chen J, Lai GGY, Oo HN, Takano A, et al. Clinical and Genomic Features of HER2 Exon 20 Insertion Mutations and Characterization of HER2 Expression by Immunohistochemistry in East Asian Non–Small-Cell Lung Cancer. JCO Precis Oncol. 2022 Oct 1;(6):e2200278.
- 15. Peters S, Stahel R, Bubendorf L, Bonomi P, Villegas A, Kowalski DM, et al. Trastuzumab Emtansine (T-DM1) in Patients with Previously Treated HER2-Overexpressing Metastatic Non–Small Cell Lung Cancer: Efficacy, Safety, and Biomarkers. Clin Cancer Res. 2019 Jan 3;25(1):64–72.
- 16. Iwama E, Zenke Y, Sugawara S, Daga H, Morise M, Yanagitani N, et al. Trastuzumab emtansine for patients with non–small cell lung cancer positive for human epidermal growth factor receptor 2 exon-20 insertion mutations. Eur J Cancer. 2022 Feb 1;162:99–106.
- 17. Song Z, Lv D, Chen SQ, Huang J, Li Y, Ying S, et al. Pyrotinib in Patients with HER2-Amplified Advanced Non–Small Cell Lung Cancer: A Prospective, Multicenter, Single-Arm Trial. Clin Cancer Res. 2022 Feb 1;28(3):461–7.
- 18. Denkert C, Seither F, Schneeweiss A, Link T, Blohmer JU, Just M, et al. Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials. Lancet Oncol. 2021 Aug 1;22(8):1151–61.
- 19. Gampenrieder SP, Rinnerthaler G, Tinchon C, Petzer A, Balic M, Heibl S, et al. Landscape of HER2-low metastatic breast cancer (MBC): results from the Austrian AGMT_MBC-Registry. Breast Cancer Res. 2021 Dec 14;23(1):112.
- 20. Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, et al. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022 Jul 7;387(1):9–20.
- 21. Beck A, Goetsch L, Dumontet C, Corvaïa N. Strategies and challenges for the next generation of antibody–drug conjugates. Nat Rev Drug Discov. 2017 May 1;16(5):315–37.
- 22. Staudacher AH, Brown MP. Antibody drug conjugates and bystander killing: is antigen-dependent internalisation required? Br J Cancer. 2017 Dec 1;117(12):1736–42.
- 23. Cooper AJ, Gainor JF. Human Epidermal Growth Factor Receptor 2–Mutant Non–Small-Cell Lung Cancer: Continued Progress But Challenges Remain. J Clin Oncol. 2022 Mar 1;40(7):693–7.
