Asco 2022 – Enhertu asks, how low can you go?

Enhertu has already delivered several outstanding results in Her2-positive breast cancer, and its latest performance does not disappoint. The antibody-drug conjugate has now shown an impressive survival benefit over chemotherapy in patients considered Her2-negative, with the data holding up even in those with the very lowest expression.

In Destiny-Breast04 Enhertu almost doubled median progression-free survival to 10.1 months over chemotherapy in women with Her2-low, estrogen receptor-positive tumours, equivalent to a 49% reduction in the risk of progression, newly released data at Asco show. Around half of all breast cancers are considered Her2 low, meaning that a major label expansion is likely on the way for the drug.

Investigators’ claim that a result was seen irrespective of estrogen receptor (ER) status is more questionable, however. Largely this is because this cohort, also known as triple-negative disease, only recruited around 60 patients, and no statistical powering was assigned to it. And a snafu that saw Asco releasing incorrect data in the abstract also raises eyebrows.

Daiichi told Evaluate Vantage that five patients were initially misclassified as ER-negative. In the abstract these remain assigned to the ER-negative group; by the time the data were presented at Asco and published in the NEJM they had been removed, and as luck would have it their removal flattered the result in the ER-negative group.

Daiichi insists that reanalysing patients' ER status had been pre-planned, and that this was not done in response to what the initial readout had shown.

“This agent is not influenced by whether you are ER positive or negative,” Gilles Gallant, head of oncology development for the Japanese drug maker, said in an interview.

Dr Jane Lowe Meisel of Emory School of Medicine said that it was tough to know whether Enhertu was having a real benefit in the ER-negative group, because of the small number of patients recruited. 

"But we have biological plausibility and a lot of reasons to think it actually works. It is an option that I would discuss with a [triple negative] patient," she said at an Asco press conference this morning.  

Destiny-Breast04 recruited an advanced population that had progressed on one or two lines of chemo and were no longer benefiting from endocrine therapy. More than a third had also been failed by CDK4/6 inhibition. Her2-low was defined as having an immunohistochemistry (IHC) score of 1+, or IHC2+ with a negative in-situ hybridisation score (ISH-).

Current guidelines dictate that these patients should be considered Her2-negative, largely because of the lack of benefit shown in this group by other Her2-targeted drugs.

Patients in the study were stratified by IHC score, and a benefit was seen regardless of this, with hazard ratios of 0.48 and 0.55 for IHC 1+ and 2+/ISH- respectively. A clear survival benefit over control, which was physician’s choice of chemo, was seen across every subgroup, according to the New England of Medicine article, which was also published today.

It was already known that the trial had also hit on overall survival, and a 6.4-month advantage is likely to be applauded by physicians when the full data are presented at Asco later today. The PFS result largely meets expectations in the financial community, and although some were hoping to see a 50% improvement in OS it would be hard to describe this result as disappointing.

Analysts reckon the Her2-low opportunity to be worth $2-3bn in annual revenue at peak, contributing around a third of Enhertu's total peak sales.

It should be noted that the drug's biggest toxicity, interstitial lung disease, once again reared its head, causing three deaths in the study. Rates of ILD, particularly high grade events, have been coming down in Enhertu trials, thanks to more intensive monitoring and education. The side effect is arguably the biggest barrier for Astra and Daiichi to overcome as they try to move the drug into earlier treatment lines.

Fatal bystander

Enhertu’s high antibody to drug ratio and strong “bystander effect”, meaning that it kills nearby cells as well as those directly hit by the ADC, are thought to contribute to its efficacy in patients with relatively few tumour cells that display the Her2 target.

It seems that IHC scoring might no longer be the best method to select patients who might benefit from Enhertu. Daiichi and Astra are trialling a different assay in a follow-up Her2-low study called Destiny-Breast06, which also includes a Her2-0 cohort.

“If you are Her2-0 it doesn’t mean you have zero receptor. It means less than 10% of cells take the stain, so there is presence of the receptor," said Daiichi's Mr Gallant. “The big question, and we haven’t determined this yet, is how low [on Her2 expression] can we go?”.

But it is clear that Destiny-Breast04 has already done the heavy lifting. The trial could establish Enhertu as the first targeted agent for a population whose only option previously was chemotherapy, and prompt previous definitions of Her2-negative cancers to be thrown out of the window.