Vigneshwari Sivakumar ’29
Lung cancer is the nation’s deadliest cancer, affecting people of all backgrounds, with the most cases of 226,650 and deaths of 124,730 this year, according to the American Cancer Society (2025). Most cancers, when detected early, can be cured and treated; however, some studies show that even with earlier diagnosis, there is no significant increase in cure or survival (Russi, 2002), which is one of the main reasons why it is deadly. This is mostly because lung cancer does not show detectable symptoms until its later stages, and, by then, it may have spread to other parts of either the lungs or the body (American Lung Association). Since early diagnosis is a challenge, a better solution for curing lung cancer is a drug or intervention that can prevent the spread and proliferation of the cancer cells, even at a later stage. According to Le et al. (2025), the deactivation of certain proteins, such as the HER2 protein, would be extremely helpful in mitigating rapid cell division and the growth of cancer tumors.
As defined by Weizmann Institute of Science researchers Rubin and Yarden, HER2 is a human epidermal growth factor receptor, situated on the surface of cells, and its primary function is to facilitate cell division when activated (2001). When the gene encoding the HER2 protein is overexpressed, it produces many copies of the protein on the cell surface, leading to rapid cell division (Rubin & Yarden, 2001). According to Riudavets et al. (2021), the increased presence and activation of HER2 are either due to gene mutation, gene amplification, or protein overexpression, with protein overexpression being one of the most common causes.
Recently, the FDA approved a new drug, sevabertinib, a kinase inhibitor that has been clinically shown to tackle the issue of HER2’s extensive signaling for rapid cell division (FDA.org). HER2 is a protein with tyrosine kinase activity, which means that it sends a signal through a pathway, and sevabertinib, being a kinase inhibitor, blocks that pathway, thus disabling the HER2 (Thomson, Moshirfar, & Ronquillo, 2023; Le et al., 2025). Since this is a novel drug, there have been many recent studies done to test its effectiveness.
One such study was conducted by Le et al. The researchers treated three cohorts of lung cancer patients. The first cohort was patients who had never received any treatment at all, the second was patients who had never received any therapy for HER2, and the third was patients who had received some HER2 treatment. The researchers had found that by roughly 8 to 9 months, there were significant results, such as the median duration of response being 9.2 months, the median progression-free survival being roughly 8.3 to 8.5 months, and around 71% of the patients showed objective responses (Le et al., 2025). According to the National Cancer Institute, progression-free survival refers to the time during which the tumor does not worsen or get bigger, and an objective response is when the tumor has undergone shrinking (National Cancer Institute). Hence, with this data obtained by Le et al., it can be seen that sevabertinib can have positive effects in mitigating lung cancer. However, with any drug, there is always a possibility of potential side effects. In the article by Le et al., it is mentioned that there were quite a few adverse events, which means negative side effects, with diarrhea being the most common one (Le et al., 2025).
Another study was conducted by Siegel et al., and it was very similar to the study by Le et al. First, the researchers had treated sevabertinib on isolated cells in the laboratory with mutations in the HER2 gene, and then administered it directly to humans with HER2 mutations, specifically the mutations with the exon 20 insertions. Exon insertion is when an exon, which is a particular component of DNA, is added to the DNA sequence (Patthy, Protein Evolution; pp. 209). Exon 20 is a particular exon that, when added, can cause uncontrollable cell division and thus lead to cancer (lung.org). When they had observed the interactions between HER2 and sevabertinib, they saw that there was ligand stabilization. As defined by Benedette Cuffari, a ligand is “any molecule or atom that irreversibly binds to a receiving protein molecule” (news-medical.net). Since sevabertinib is a tyrosine kinase inhibitor, this ligand stabilization allows for a pause in the signaling pathway, thus reducing cell division. The article itself states that these results show that sevabertinib is “a highly efficacious reversible binder,” or can strongly reduce the activity of HER2 while also not being permanent, thus allowing for some adjustments if needed. The study further observed the effects of sevabertinib on two patients (one male and one female). Both of the patients had been undergoing treatment other than sevabertinib before this study. The results show that the female patient had an increase in tumor shrinkage up to 30 weeks, with the maximum being 53% tumor shrinkage. After 30 weeks, progressive disease, or that which indicates the tumor is becoming worse, was detected. For the male patient, the results were quite similar, with a 78% tumor shrinkage by week 54; however, progressive disease was detected after 80 weeks (Siegel et al., 2025).
From both of these studies, it can be seen that sevabertinib indeed has promising results in mitigating lung cancer. From Le et al.’s paper, we saw that sevabertinib has objective responses, similar to Siegel et al.’s study, where the patients had tumor shrinkage to an extent. However, Siegel et al. suggest that sevabertinib cannot be a permanent solution to clearing off the tumor. While both sets of researchers agree that sevabertinib’s positive effects lasted for either a couple of months or weeks, Siegel et al. noted that the tumors worsened later. The article does not explicitly mention if there is a particular reason, but it can be generally inferred that resistance and other mutations could have likely diminished the effectiveness of sevabertibin. The FDA, on its main page, does not explicitly mention the possibility of disease progression, but does align with the findings of both Le et al. and Siegel et al., including the adverse effects and the average objective response.
In essence, there is a promising outlook when it comes to tackling lung cancer. As mentioned before, sevabertinib mainly targets the HER2 protein, whose activity can most likely be detected in later stages of lung cancer. Since delayed detection was a constant challenge to combating lung cancer, this drug allows for mitigation, even when it might have been thought of as “too late” in the past. Now, patients can have more hope for tumor shrinkage and hopefully, a cure. Indeed, sevabertinib is a very new drug in the industry, and awaits more trials and experiments to ensure that, even if it does not reach perfection, it can compress tumors for a bit longer, as it aids the other traditional treatments for cancer.
Vigneshwari Sivakumar is a staff writer at The Princeton Medical Review. She can be reached at vs7850@princeton.edu.
References
American Cancer Society. (2025, January 16). Key statistics for lung cancer. https://www.cancer.org/cancer/types/lung-cancer/about/key-statistics.html
American Lung Association. (n.d.). Key findings: State of Lung Cancer. American Lung Association. https://www.lung.org/research/state-of-lung-cancer/key-findings
Association, American Lung. “EGFR Exon 20 Insertion Mutation and Lung Cancer.” Www.lung.org, www.lung.org/lung-health-diseases/lung-disease-lookup/lung-cancer/symptoms-diagnosis/biomarker-testing/egfr/egfr-exon-20-insertion-mutation.
Cuffari, Benedette. “What Are Ligands?” News-Medical.net, 9 Oct. 2020,
www.news-medical.net/life-sciences/Ligands-An-Overview.aspx.
Le, X., Kim, T. M., Loong, H. H., Prelaj, A., Goh, B. C., Li, L., … & Tan, D. S. W. (2025). Sevabertinib in advanced HER2-mutant non–small-cell lung cancer. New England Journal of Medicine, 393(18), 1819-1832.
National Cancer Institute. (n.d.). Dictionary of Cancer Terms. U.S. Department of Health and Human Services. https://www.cancer.gov/publications/dictionaries/cancer-terms/
Riudavets, M., Sullivan, I., Abdayem, P., & Planchard, D. (2021). Targeting HER2 in non-small-cell lung cancer (NSCLC): a glimpse of hope? An updated review on therapeutic strategies in NSCLC harbouring HER2 alterations. ESMO Open, 6(5), 100260.
Patthy, L. (2009). Protein evolution. John Wiley & Sons.
Rubin, I., & Yarden, Y. (2001). The basic biology of HER2. Annals of Oncology, 12, S3-S8.
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Siegel, F., Siegel, S., Kotýnková, K., Karsli Uzunbas, G., Korr, D., Tomono, H., … & Greulich, H. (2025). Sevabertinib, a Reversible HER2 Inhibitor with Activity in Lung Cancer. Cancer Discovery, OF1-OF14.
Thomson, RJ., Moshirfar, M., Ronquillo Y. Tyrosine Kinase Inhibitors. [Updated 2023 Jul 18]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK563322/
U.S. Food and Drug Administration. (2025, November 19). FDA grants accelerated approval to sevabertinib for non-squamous non-small-cell lung cancer. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-sevabertinib-non-squamous-non-small-cell-lung-cancer
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