Enhertu (trastuzumab deruxtecan), a HER2-targeting antibody-drug conjugate (ADC) bearing a deruxtecan (TOP1 inhibitor) warhead, was developed by Japanese pharmaceutical company Daichi Sankyo. A collaboration with AstraZeneca for the drug’s further development and commercialisation was established in 2019.

Enhertu is the second HER2-targeting ADC approved by the US Food and Drug Administration (FDA) after Roche’s Kadcyla (ado-trastuzumab etamine), which was approved in 2013 for HER2-positive (HER2+) unresectable or metastatic breast cancer in the second line. Kadcyla is also approved as an adjuvant therapy for early breast cancer patients with residual disease. Enhertu has a drug antibody ratio (DAR) of eight, compared to Kadcyla’s mean DAR of 3.5, making Enhertu more cytotoxic.

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Unlike Kadcyla, Enhertu elicits a bystander effect, with the deruxtecan warhead diffusing into tumour antigen-negative cells, making it a suitable therapy for cancers with heterogenous HER2 expression. The bystander effect also enables the killing of non-cancer elements of the tumour such as stromal or vascular cells, which further increases the tumour-killing potential. The high DAR and the bystander effect make Enhertu a promising therapeutic for cancers with low or heterogenous HER2 expression, giving it a clinical edge over Kadcyla.

In 2019, the FDA granted approval for the use of Enhertu in HER2+ breast cancer patients with unresectable or metastatic disease who had progressed on two prior lines of therapy. Enhertu’s label is set to expand, replacing Kadcyla as a second-line therapy for unresectable or metastatic HER2+ breast cancer. That October, the FDA had granted Enhertu breakthrough therapy designation (BTD) as a second-line therapy for HER2+ unresectable or metastatic breast cancer based on the DESTINY-Breast03 Phase III trial, which showed the drug to be superior to Kadcyla.

The 12-month progression free survival (PFS) was 75.8% with Enhertu compared to 34.1% with Kadcyla, while the overall response rate (ORR) for Enhertu was 79.7% compared to 34.2% with Kadcyla. Daichi Sankyo and AstraZeneca are also investigating Enhertu in the first line, with a Phase II trial set up earlier this year. Future label expansion for Enhertu also include competing with Kadcyla in the adjuvant HER2+ breast cancer setting for patients with residual disease, with the DESTINY-Breast05 trial performing a head-to-head comparison of the two ADCs.

Multiple clinical trials are also investigating the use of Enhertu for HER2-low (IHC1/2+ and FISH-) unresectable or metastatic breast cancers. Data from a Phase Ib trial reported a confirmed ORR of 37% with a median duration of response (DOR) of 10.4 months, suggesting this to be a potential therapeutic for this subset of patients. There are currently no approved HER2-targeting therapies for this indication.

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In January 2021, Enhertu received FDA approval for the treatment of locally advanced and metastatic gastric or gastric oesophagal junction (GEJ) adenocarcinoma that had progressed on a prior trastuzumab-based regimen. This was based on the DESTINY-Gastric01 Phase II study, which showed overall survival (OS) benefit of four months compared to standard of care (SOC) chemotherapy. This shows its superiority to Kadcyla, which showed no survival benefit when compared to SOC chemotherapy in the Phase III GATSBY study.

Current evidence shows Enhertu to be a best-in-class HER2-targeting ADC, with the drug set to take the largest class share ahead of Kadcyla. In the HER2+ breast cancer setting, GlobalData forecasts annual revenue in the eight major markets (8MM, namely the US, France, Germany, Italy, Spain, UK, Japan and China) to exceed $1.42bn by 2030. Daichi Sankyo and AstraZeneca have a diversified clinical development programme for Enhertu across multiple indications, including non-small cell lung cancer, triple-negative breast cancer, HER2+ urethral cancer, HER2+ osteosarcomas, HER2+ endometrial cancer and HER2+ colorectal cancers. Several trials are exploring the use of Enhertu in combination with AstraZeneca’s anti-programmed death-ligand 1 (PD-L1) Imfinzi (durvalumab), after research by Daichi Sankyo showed that treatment with Enhertu increased tumour-infiltrating immune cells and tumour PD-L1 expression. A combination of the two therapies would further increase revenue for AstraZeneca.