By: Nivaj Haque; PharmD Candidate c/o 2027

In recent years, advancements in oncology have transformed the treatment landscape for various cancers, including those overexpressing human epidermal growth factor receptor 2 (HER2). Approximately 15-20% of breast cancers and a significant proportion of gastric and lung cancers are HER2-positive, making this a critical target for innovative therapies.¹ These cancers tend to be more aggressive and have poorer prognosis compared to HER2-negative cancers, necessitating the development of more effective treatments.²

Recommendations for the treatment of HER2-positive cancers are established by prominent organizations such as the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN). These organizations recommend a combination of targeted therapies and chemotherapy as first-line treatment for HER2-positive cancers. In addition to traditional chemotherapy, targeted therapies like trastuzumab (Herceptin) and pertuzumab (Perjeta) have been instrumental in improving outcomes for patients.^3,4 These guidelines emphasize the importance of personalized treatment plans based on the individual characteristics of each patient’s cancer, incorporating the latest advances in targeted therapy to optimize outcomes.

HER2-positive cancers result from the overexpression of the HER2 protein, which promotes the growth and spread of cancer cells. This overexpression is linked to a higher likelihood of recurrence and resistance to conventional therapies.⁵ The introduction of targeted treatments has provided new hope for patients, significantly improving survival rates and quality of life.

One of the most promising therapies in this area is fam-trastuzumab deruxtecan-nxki (Enhertu), a HER2-directed antibody and topoisomerase inhibitor conjugate, developed by Daiichi Sankyo and AstraZeneca. Enhertu received accelerated approval from the FDA for the treatment of HER2-positive breast cancer in December 2019, and its indications have since expanded. On January 15, 2024, the FDA granted accelerated approval for Enhertu to treat any HER2-positive solid tumor that has progressed following prior treatment or for which there are no satisfactory alternative treatment options.⁶

Enhertu’s mechanism of action involves binding to the HER2 receptor on cancer cells, delivering a cytotoxic payload directly into the cell, thereby inducing cell death. This targeted approach helps to minimize damage to healthy cells, making it a potent and precise treatment option.⁷ Enhertu is administered via intravenous infusion. The recommended dose is 5.4 mg/kg every three weeks until disease progression or unacceptable toxicity. Common side effects include nausea, fatigue, vomiting, alopecia, constipation, and neutropenia. Serious adverse reactions, such as interstitial lung disease and pneumonitis, require careful monitoring and management.⁶

Clinical trials have demonstrated the efficacy of Enhertu across various HER2-positive cancers. The DESTINY-PanTumor02 trial, a significant multicenter, open-label, single-arm study, evaluated the efficacy and safety of Enhertu in patients with advanced HER2-positive solid tumors. This trial enrolled 276 patients with various HER2-expressing tumors, including breast, gastric, colorectal, and non-small cell lung cancers, among others. The primary endpoint was the objective response rate (ORR), with secondary endpoints including duration of response (DoR), progression-free survival (PFS), and overall survival (OS).⁸

Key findings from the trial included an investigator-assessed ORR of 37% in a heavily pretreated patient population, with a median DoR of 11.8 months. Additionally, the study highlighted that patients with higher HER2 expression (IHC 3+) had an even higher ORR of around 61%, with a DoR of 22.1 months. The ORR across all tumor types was 45.3%, with a median DoR of 11.3 months. The median PFS was 8.2 months, and the median OS was 14.7 months.⁸ These results highlight Enhertu’s potential to provide meaningful clinical benefits to patients with HER2-positive solid tumors, regardless of the tumor’s origin.

The accelerated approval of Enhertu for the treatment of HER2-positive solid tumors marks a significant advancement in oncology. It provides a new treatment option for patients with difficult-to-treat cancers, offering hope for improved outcomes. Continued studies and real-world evidence will further define Enhertu’s role in the treatment landscape and may lead to full approval based on confirmatory trial results.

References

1. Hou Y, Nitta H, Li Z. HER2 Intratumoral Heterogeneity in Breast Cancer, an Evolving Concept. Cancers. 2023;15(10):2664. doi:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10216596/
2. Hofheinz R, Lorenzen S, Bohlmann MK. HER-2-Positive Tumors: A Continuously Evolving Field in Cancer Research. Cancers. 2023;15(13):3333-3333. doi::https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10341063/
3. Robinson P. Neoadjuvant/Adjuvant Treatment for HER2-Positive Breast Cancer with SABCS Updates. NCCN.org . Published 2024. https://education.nccn.org/sites/default/files/course/2024-02/03_Robinson_NCCNbc24_v3.pdf
4. Targeted Drug Therapy | Breast Cancer Treatment. www.cancer.org. Published November 28, 2023. https://www.cancer.org/cancer/types/breast-cancer/treatment/targeted-therapy-for-breast-cancer.html
5. Tai W, Mahato R, Cheng K. The role of HER2 in cancer therapy and targeted drug delivery. Journal of Controlled Release. 2010;146(3):264-275. doi:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2918695/
6. Center. FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for. U.S. Food and Drug Administration. Published 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-fam-trastuzumab-deruxtecan-nxki-unresectable-or-metastatic-her2
7. DrugBank. Trastuzumab. go.drugbank.com. Published 2005. https://go.drugbank.com/drugs/DB00072
8. Enhertu demonstrated clinically meaningful and durable responses in patients across multiple HER2-expressing advanced solid tumors. www.astrazeneca.com. Published June 5, 2023. Accessed July 21, 2024. https://www.astrazeneca.com/media-centre/press-releases/2023/enhertu-demonstrated-clinically-meaningful-and-durable-responses-in-patients-across-multiple-her2-expressing.html