Examining Current & Potential Targets for Treating EGFR-Mutated Non-Small Cell Lung Cancer

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Sponsored by Daiichi Sankyo

Sponsored by Daiichi Sankyo

EGFR-Mutated Non-Small Cell Lung Cancer

Lung cancer is the third most common cancer and the leading cause of cancer-related deaths in the United States.1 Approximately 226,000 new cases of lung cancer were diagnosed in 2022 in the United States, with non-small cell lung cancer (NSCLC) accounting for approximately 81% of all cases.1,2

Among those with NSCLC (adenocarcinoma), human epidermal growth factor receptor (EGFR) mutations are common, occurring in approximately 1 in 5 patients in Western populations, and cause uncontrolled signaling that drives the proliferation of cancer cells.3,4

Current Treatment Options

Third-generation EGFR tyrosine kinase inhibitors (TKIs) are the first-line standard of care for patients with EGFR-mutated metastatic NSCLC due to their effectiveness in inhibiting EGFR hyperactivity, thereby slowing the proliferation of cancer cells.5 Despite initial response, patients inevitably develop resistance to EGFR TKI treatments and their disease progresses.4

After disease progression following treatment with third-generation EGFR TKIs, second- and third-line treatments for NSCLC patients fall short.6-8 The addition of immunotherapy to standard platinum-based chemotherapy has failed to demonstrate meaningful improvements in metastatic NSCLC, and salvage chemotherapy has been shown to result in worse outcomes for patients.6,7 Meanwhile, limited data exist to support the recycling of EGFR TKI treatment following progression.8

Additional options are needed for patients whose disease has progressed following first-line treatment.5

Potential New Strategies

Research has shown that several targets may have the potential to overcome resistance mechanisms in EGFR-mutated metastatic NSCLC.

A cell surface protein known as HER3 is one such potential target.9 HER3 is expressed in about 83% of primary NSCLC tumors and is overexpressed in secondary metastases, including lymph nodes and brain tissue, with lower expression on healthy cells.10,11

The gene mesenchymal epithelial transition (MET) may be another target for a specific form of EGFR TKI resistance.12 MET amplification can represent a secondary resistance mechanism in response to EGFR TKIs, with a 15% incidence of upregulation observed following EGFR TKI resistance, and activate the STAT, MAPK, and PI3K pathways to promote cancer growth.13

Finally, adaptive mechanisms of resistance to third-generation EGFR TKIs can also occur, known as C797S mutations. These mutations have been observed in 7% to 22% of cases following resistance to a third-generation EGFR TKI after first- and second-line treatment.14 More research is needed to understand if targeting these mutations will help address specific forms of resistance to third-generation EGFR TKIs.14

Continuing to Address an Unmet Need

While there remains significant unmet need for post-progression treatments among patients with EGFR-mutated metastatic NSCLC, ongoing research and clinical developments are bringing us closer to providing patients with more options. Daiichi Sankyo is committed to finding ways to help patients after progression.

For more information on EGFR-mutated mNSCLC please visit egfrmnsclc.com.

References

  1. Global Cancer Observatory. U.S. Cancer Fact Sheet. Accessed March 2024. https://gco.iarc.who.int/media/globocan/factsheets/populations/840-united-states-of-america-fact-sheet.pdf
  2. Lung Cancer – Non-Small Cell: Statistics. Cancer.net. Reviewed March 2023. Accessed March 2024. https://www.cancer.net/cancer-types/lung-cancer-non-small-cell/statistics
  3. Tan AC, Tan DSW. Targeted therapies for lung cancer patients with oncogenic driver molecular alterations. J Clin Oncol. 2022;40(6):611-625.
  4. Passaro A, Jänne PA, Mok T, Peters S. Overcoming therapy resistance in EGFR-mutant lung cancer. . 2021;2(4):377-391. doi:10.1038/s43018-021-00195-8
  5. Johnson M, Grassiano MC, Mok T, Mitsudomi T. Treatment strategies and outcomes for patients with EGFR-mutant non-small cell lung cancer resistant to EGFR tyrosine kinase inhibitors: focus on novel therapies. . 2022;170:41-51. doi:10.1016/j.lungcan.2022.05.011
  6. Yang CJ, Hung JY, Tsai MJ, et al. The salvage therapy in lung adenocarcinoma initially harbored susceptible EGFR mutation and acquired resistance occurred to the first-line gefitinib and second-line cytotoxic chemotherapy. . 2017;18(1):21. doi:10.1186/s40360-017-0130-0
  7. Mok TSK, Nakagawa K, Park K, et al. LBA8 Nivolumab (NIVO) + chemotherapy (chemo) vs chemo in patients (pts) with EGFR-mutated metastatic non-small cell lung cancer (mNSCLC) with disease progression after EGFR tyrosine kinase inhibitors (TKIs) in CheckMate 722. Ann Oncol. 2022;33(9):S1561-S1562. doi:10.1016/j.annonc.2022.10.350
  8. Aredo JV, Wakelee HA, Neal JW, Padda SK. Afatinib after progression on osimertinib in EGFR-mutated non-small cell lung cancer. Cancer Treat Res Commun. 2022;30:100497. doi:10.1016/j.ctarc.2021.100497
  9. Gaborit N, Lindzen M, Yarden Y. Emerging anti-cancer antibodies and combination therapies targeting HER3/ERBB3. Hum Vaccin Immunother. 2016;12(3):576-592. doi:10.1080/21645515.2015.1102809
  10. Inaki K, Shibutani T, Maeda N, et al. Pan-cancer gene expression analysis of tissue microarray using EdgeSeq oncology biomarker panel and a cross-comparison with HER2 and HER3 immunohistochemical analysis. PLoS One. 2022;17(9):e0274140. doi:10.1371/journal.pone.0274140
  11. Scharpenseel H, Hanssen A, Loges S, et al. EGFR and HER3 expression in circulating tumor cells and tumor tissue from non-small cell lung cancer patients. Sci Rep. 2019;9(1):7406. doi:10.1038/s41598-019-43678-6
  12. Girard N. New strategies and novel combinations in EGFR-TKI-resistant non-small cell lung cancer. Curr Treat Option Oncol. 2022;23(11):1626-1644
  13. Di Noia V, D’Aveni A, D’Argento E, et al. Treating disease progression with osimertinib in EGFR-mutated non-small-cell lung cancer: novel targeted agents and combination strategies. ESMO Open. 2021;6(6):100280. doi: 10.1016/j.esmoop.2021.100280
  14. Ríos-Hoyo A, Moliner L, Arriola E. Acquired mechanisms of resistance to osimertinib–the next challenge. Cancers (Basel). 2022;14(8):1931. doi:10.3390/cancers14081931

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04/24