Enhertu tightens its stranglehold

The $1.4bn that Astrazeneca gave Daiichi Sankyo three years ago for Enhertu, a seemingly large sum for what was then a mid-stage clinical hope, is increasingly looking like money well spent. The antibody-drug conjugate keeps acing key trials, and is seemingly on course to become a foundational breast cancer therapy.

The latest success, toplined this morning, was in Her2-low breast cancer courtesy of the Destiny-Breast04 study, which has hit not only its primary progression-free survival endpoint but the all-important overall survival metric too. The relevance of Her2-low disease should not be underestimated, though just how big an opportunity it might represent for Enhertu depends on the full dataset.

The standard for Her2-targeting drugs like Enhertu was set years ago by Roche’s Herceptin, and has been followed by Perjeta, Kadcyla, Macrogenics’ Margenza and Seagen’s Tukysa, namely that these should be used in Her2-overexpressing breast cancer. Overexpression has been defined as cancer in which cell surface Her2 scores 3+ via an immunohistochemistry (IHC) assay.

A score below 3+ would technically be defined as non-expression or borderline Her2 expression, and Herceptin and the like cannot be used in these patients. It is here that Enhertu has yielded its latest breakthrough: Destiny-Breast04 enrolled patients scoring 1+ or 2+.

Around 15% of breast cancers are thought to be Her2 overexpressing; Her2-low tumours might account for two thirds of the remainder. This is a space that Zymeworks, for instance, had earlier tried to target, but toxicity concerns appear to have set it back.

No practice change

The good news is that, with Her2 testing already standard in breast cancer, approval and use of Enhertu in Her2-low patients should not necessitate a huge change in medical practice. But just how big an opportunity this represents is not entirely clear, as Astra/Daiichi have revealed no detailed analysis from Destiny-Breast04.

A key analysis will be to split IHC 1+ from 2+ expressers, as a miss in the former might result in doctors being reluctant to prescribe Enhertu to patients expressing Her2 below the IHC 2+ level.

Enhertu has accelerated approval for third-line Her2-overexpressing breast cancer, and after a storming win in the second-line Destiny-Breast03 trial at last year’s Esmo conference it appears set for approval here too. Two weeks ago Astra confirmed that a second-line filing had been submitted in the fourth quarter.

Meanwhile, Destiny-Breast04 enrolled low Her2 expressers who had progressed on one or two prior therapy lines, though Astra will use it to back an initial third-line filing, due by the mid-year. A separate second-line study in Her2-low patients, Destiny-Breast06, is to read out next year.

In Destiny-Breast04 Enhertu was compared against physician’s choice chemotherapy, and investors will have to wait for a medical meeting to find out the extent of its PFS and OS success. Analysts had expected a PFS improvement of at least three months over chemo, which typically yields PFS in the three to five-month range in these patients.

One caveat is interstitial lung disease, about which Enhertu's current label carries a boxed warning. Astra said deaths due to this occurred at a "lower rate" in Destiny-Breast04, but again full data will give the necessary context.

A separate analysis should show how Enhertu performed in ER-positive versus ER-negative patients; both were eligible for Destiny-Breast04. The distinction is important because breast cancer patients can still benefit from a variety of drugs in the Her2-negative/ER-positive setting.

Loss of ER expression deems them triple-negative, a particularly aggressive phenotype. But the hope might be that a significant portion of these technically triple-negative patients who nevertheless do express low levels of Her2 might soon be able to benefit from Enhertu, a scenario that could be the cherry on the cake for the Astra/Daiichi drug.

Enhertu’s perceived superiority has already caused forecasts for Seagen’s Tukysa to crash. Roche’s Her2 franchise, which recorded sales of around $9.5bn last year, could eventually come under pressure too, and if Enhertu becomes an option in patients ineligible for the Roche drugs its 2026 sellside forecasts of $4.0bn could look achievable.