AstraZeneca, Daiichi Sankyo launch Enhertu head-to-head trial with eyes on a new breast cancer standard

AstraZeneca and Daiichi Sankyo have high hopes for their HER2-targeted drug Enhertu and are planning a long list of clinical trials in several diseases to capitalize on its multibillion-dollar potential.

The latest? A head-to-head phase 3 trial that aims to establish the antibody-drug conjugate (ADC) as the new standard of care in newly diagnosed HER2-positive metastatic breast cancer.

The pair on Monday said they have dosed the first patient in the Destiny-Breast09 trial, which is comparing Enhertu—with or without Roche’s Perjeta—against a triplet combo that includes Perjeta, Roche’s aging Herceptin and chemotherapy.

Trial investigators plan to enroll 1,134 patients across six continents. On its primary goal, the study will evaluate whether Enhertu can extend the time patients live without disease progression as assessed by a blinded independent review committee. Other secondary measures include whether the drug can prolong patients’ lives, time to second progression or death and health-related quality of life, among others.

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Enhertu scored its first FDA approval in late 2019 to treat HER2-positive metastatic breast cancer after at least two prior therapies. An update earlier this year expanded the label to include previously treated stomach cancer.

Destiny-Breast09 represents AZ and Daiichi’s latest effort to try to bring Enhertu either earlier in the treatment line—or into different cancers. 

In November, the two drugmakers launched the Destiny-Breast05 trial, pitting Enhertu against Roche’s ADC Kadcyla as a post-surgery adjuvant treatment for early-stage, HER2-positive breast cancer patients who are at a high risk of disease recurrence.

Meanwhile, AZ and Daiichi are also expecting data later this year from Destiny-Breast03. If successful, that trial could move the ADC to second-line HER2-positive breast cancer. Next year, the Destiny-Breast04 study will determine whether Enhertu works in HER2-low breast cancer. Studies of triple-negative breast cancer, non-small cell lung cancer and colorectal cancer are also underway.

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Enhertu, the target in a 2019 licensing deal between AZ and Daiichi worth up to $6.9 billion, bears megablockbuster hopes and leads Daiichi’s big pivot to oncology. The drugmaker hopes its cancer portfolio can haul in JPY 600 billion ($5.5 billion) in the fiscal year that ends in March 2026, according to a new five-year plan unveiled in April.

Still, a front-line breast cancer label expansion likely won’t contribute to that mid-term projection because Destiny-Breast09 bears a primary completion date in mid-2025.

On its blockbuster path, Enhertu is competing against Roche’s leading HER2 franchise—including off-patent Herceptin—as well as small-molecule drugs such as Seagen’s Merck & Co.-partnered Tukysa. In 2020, Roche’s HER2 portfolio racked up sales of CHF 9.38 billion ($10.4 billion) despite an 8% decline caused by COVID-19 and Herceptin biosimilars.

Currently, U.S. physicians treat about a third of their third-line HER2-positive metastatic breast cancer patients with Enhertu, according to a recent survey by Jefferies. Among those who’re not using the drug, 84% cited the side effects of pneumonitis or interstitial lung disease as their main reasons for the decision. For Enhertu to significantly penetrate the front- or second-line breast cancer settings, an acceptable interstitial lung disease rate could fall at around 5%, two breast cancer experts recently told SVB Leerink.

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In their March note, Jefferies’ analysts project a 100% success rate for Enhertu in the second-line trial. About 31% of doctors will use the drug three years after a green light in that setting, the survey showed.

Overall, in five years’ time, the doctors Jefferies polled expect their general use of Enhertu in all HER2-positive breast cancer patients to rise to 39%, up from 14% today.

“In our view, this suggests that doctors currently using Enhertu in the 3rd-line setting must think it is a good treatment as they believe they will be using considerably more Enhertu as it moves to earlier lines of therapy,” the analysts wrote in the note.