At the American Society of Clinical Oncology (ASCO) Annual Meeting, 2-6 June 2023, interim results were presented for the Phase II DESTINY-Pan Tumor02 study investigating AstraZeneca’s and Daiichi’s Enhertu (trastuzumab deruxtecan) in a broad range of HER2-expressing solid tumours. The study enrolled 267 oncology patients with HER2 immunohistochemistry (IHC)-positive disease (IHC 2+ or IHC 3+) with cervical cancer (40), endometrial cancer (40), ovarian cancer (40), biliary tract cancer (41), pancreatic cancer (25), bladder cancer (41), and other cancers (40). Patients in the study received Enhertu at a dose of 5.4mg/kg every three weeks. Patients enrolled in the study had received a median of two prior lines of therapy.
The study reported an impressive overall response rate (ORR) of 37.1%, with 5.6% of patients achieving a complete response and 31.5% achieving a partial response. A further 46.1% of patients had stable disease as the best response. Importantly, responses were durable, with a median duration of response (mDoR) of 11.8 months. The results were even more dramatic for the subgroup of patients with IHC 3+ disease, with a confirmed ORR of 61.3% and a mDoR of 22.1 months. When comparing different disease sites, the response rates were particularly notable in gynaecological cancers, with ORRs of 50%, 57.5%, and 45% for cervical, endometrial, and ovarian cancer, respectively. This ORR sequence continued with bladder cancer (39%), other cancers (30%), biliary tract cancer (22%), and pancreatic cancer (4%). The safety profile of Enhertu in this study was consistent with previous studies. Drug-related treatment-emergent adverse events (TEAEs) occurred in 38.6% of patients, with 12% experiencing serious drug-related TEAEs. Drug-related TEAEs that occurred in more than 10% of patients included nausea, fatigue, neutropenia, anaemia, diarrhoea, vomiting, decreased appetite, thrombocytopenia, alopecia, and leukopenia. There were two reported treatment-related deaths due to neutropenia-related sepsis and pneumonia.
Enhertu is a HER2-targeting antibody-drug conjugate (ADC) made up of an anti-HER2 monoclonal antibody linked to a topoisomerase I inhibitor payload, deruxtecan. The ADC was developed by Daiichi Sankyo, with a collaboration with AstraZeneca established in 2019 for its further development and commercialization. Enhertu has a high drug antibody ratio, with eight deruxtecan molecules conjugated to each mAb, making Enhertu more cytotoxic than many other ADCs. In addition, 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 tumour elements, such as stromal or vascular cells, further increasing the tumour-killing potential.
Enhertu is currently approved for HER2-positive breast cancer, HER2-positive gastric or gastroesophageal cancer, HER2-low breast cancer, and HER2-mutant non-small cell lung cancer (NSCLC). While targeting HER2 is a well-established approach for patients with breast cancers and gastric or gastroesophageal cancers expressing high levels of HER2, Enhertu is the first HER2-directed therapy to gain approval for HER2-low-expressing breast cancer and HER2-mutant NSCLC. Furthermore, there are currently no approved anti-HER2 therapies for the solid tumours investigated in the DESTINY-Pan Tumor02 study. Data from this study demonstrates the potential for Enhertu to achieve a tumour-agnostic label, which would be a first for any ADC. Tumour-agnostic approval would lead to increased sales for Enhertu, which already achieved blockbuster status in 2022, with global sales exceeding $1.6bn. GlobalData’s consensus forecast projects global sales for Enhertu to exceed $9.9bn by 2029, driven by increased uptake for already approved indications across markets and expansion into new indications.
