Daiichi Sankyo and AstraZeneca have announced positive results from the ongoing DESTINY-Pan Tumor02 Phase II study. Enhertu (trastuzumab deruxtecan) has met the prespecified target for the primary endpoint of objective response rate (ORR) and has demonstrated durable responses across multiple HER2-expressing solid tumor types in heavily pretreated patients. The study included 268 patients with biliary tract, bladder, cervical, endometrial, ovarian and pancreatic cancers, for all of which no curative therapy was available. Patients enrolled in the study were treated with Enhertu at a dose of 5.4mg/kg, with the safety profile of the drug being consistent with that seen in other trials investigating Enhertu.
Enhertu is a HER2-targeting antibody-drug conjugate (ADC) consisting of an anti-HER2 monoclonal antibody (mAb) linked to a topoisomerase I inhibitor payload, deruxtecan. The ADC was developed by Daiichi Sankyo, with a collaboration with AstraZeneca established in 2019 for the further development and commercialisation of the ADC. The ADC 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). Targeting HER2 is a well-established approach for patients with breast cancers and gastric or gastroesophageal cancers expressing high levels of HER2, with several anti-HER2 therapies approved in these settings. However, Enhertu is the first HER2-directed therapy to gain approval for HER2-low-expressing breast cancer and HER2-mutant NSCLC. Furthermore, in a head-to-head comparison in the HER2-positive breast cancer setting, Enhertu outperformed the only other marketed HER2-targeting ADC, Roche’s Kadcyla (trastuzumab etamine).
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Enhertu has a high drug antibody ratio (DAR), with eight deruxtecan molecules conjugated to each mAb. This makes Enhertu more cytotoxic than many other ADCs, including its competitor Kadcyla, which has a mean DAR of 3.5. In addition, Enhertu elicits a bystander effect, with the deruxtecan warhead diffusing into tumor antigen-negative cells, making it a suitable therapy for cancers with heterogenous HER2 expression. The bystander effect also enables the killing of non-cancer tumor elements, such as stromal or vascular cells, further increasing the tumor-killing potential. The high DAR and the bystander effect make Enhertu an effective therapy for cancers with low or heterogenous HER2 expression, enabling treatment of a much broader range of tumours than other anti-HER2 therapeutics.
Enhertu achieved blockbuster status in 2022, with global sales exceeding $1.2bn driven by breast cancer and gastric and gastroesophageal cancer, and to a lesser extent, NSCLC. GlobalData’s consensus forecast projects global sales for Enhertu to reach $9.9bn by 2028, with this driven by increased uptake for already approved indications across markets and expansion into new indications. The positive data from DESTINY-Pan Tumor02 shows the potential for Enhertu to become a tumor-agnostic therapeutic, targeting any HER2-expressing cancer; this will both boost sales for the best-in-class ADC, as well as provide an effective therapeutic option for patients with minimal treatment choices.
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