Blockbuster Enhertu may get tumor agnostic label, targeting any HER2-expressing cancer: GlobalData

Daiichi Sankyo and AstraZeneca recently announced positive results from the ongoing DESTINY-Pan Tumor02 Phase II study, which included 268 patients with biliary tract, bladder, cervical, endometrial, ovarian, pancreatic, and other rare cancers, for all of whom no curative therapy was available. The study revealed that Enhertu met the prespecified target for the primary endpoint of objective response rate (ORR) and demonstrated durable responses across multiple HER2-expressing solid tumor types in heavily pretreated patients. This is a very significant milestone for the antibody-drug conjugate (ADC), with no HER2-directed therapy previously demonstrating efficacy in these tumor types, according to GlobalData.

Dr Avigayil Chalk, Oncology & Hematology Analyst at GlobalData, comments, “Enhertu is a HER2-targeting ADC consisting of an anti-HER2 monoclonal antibody (mAb) linked to a topoisomerase I inhibitor payload, deruxtecan. 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.”

Enhertu is the second HER2-directed ADC to gain regulatory approval, with Roche’s Kadclya FDA-approved for HER2-positive breast cancer in 2013. In a head-to-head comparison in the second-line metastatic HER2-positive breast cancer setting, Enhertu outperformed Kadcyla with a 12-month progression-free survival (PFS) of 75.8 per cent versus 34.1 per cent.

Chalk continues, “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 tumors than other anti-HER2 therapeutics.”

Enhertu achieved blockbuster status in 2022, with global sales exceeding $1.2 billion. Breast cancer was the driving indication, followed by gastric and gastroesophageal cancer, and to a lesser extent NSCLC.

GlobalData’s consensus forecast projects global sales for Enhertu to reach $9.9 billion by 2028.

Chalk adds, “Huge growth in sales will come from 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.”