ASCO 2024 – Enhertu nears its “ultralow” dream

A virtually identical progression-free survival outcome has been shown in Enhertu’s Destiny-Breast06 trial in HER2-low and HER2-ultralow patients, something that could open up the lucrative “ultralow” niche for the drug’s makers, Daiichi Sankyo and AstraZeneca.

This was the hope since the study was toplined positive in April, and it quickly secured its place as a late-breaker at this weekend’s conference. The data, unveiled in full today, could dispel fears that HER2-low patients were driving the overall benefit, especially as on two other measures “ultralows” have numerically done at least as well.

One stumbling block to approval in HER2-ultralow breast cancer is the fitness of current testing for HER2 status, seen by some to be inadequate even for straightforward determination of HER2 positivity, let alone the determination whether a patient expresses vanishingly low levels of this protein.

At a press briefing before today’s ASCO presentation Johns Hopkins University’s Dr Aditya Bardia, one of Destiny-Breast06’s authors, said the current immunohistochemistry (IHC) assay was designed to identify high expressing HER2-positive tumours, not those with lower expression levels. “We need better assays,” he stated. 

Astra reckons that 60-65% of ER-positive breast cancers traditionally classified as HER2-negative are in fact HER2-low, whereas HER2-ultralow might account for another 20-25%. The remainder show no HER2 membrane staining.

It’s also unclear whether the FDA will see a benefit on PFS alone as sufficient for such a significant broadening of Enhertu’s label, especially given what the press conference discussant, Dana-Farber’s Dr Erica Mayer, called “the toxicity issue”.

Three of the 436 patients enrolled into Destiny-Breast06’s Enhertu treatment arm died of interstitial lung disease, for instance. Mayer was careful not to describe this trial as practice-changing, and expressed caution about its relevance in a broad population, saying Enhertu might not be suitable for everyone.

Overall survival

On the survival point at least ASCO has provided comfort. A landmark 12-month OS analysis of the trial has yielded a 17% reduction in risk of death among HER2-low patients, 19% among Destiny-Breast06 all-comers, and 25% in HER2-ultralow patients. This immature analysis lacks statistical significance, but the highly positive way the HER2-ultralows are shaping up won’t go unnoticed. 

Destiny-Breast06 recruited a pre-chemotherapy population that had progressed after first-line treatment with a CDK4/6 inhibitor plus endocrine therapy, or two lines of endocrine therapy. Thus its main aim was to advance Enhertu into an earlier setting versus its current approval in HER2-low patients after chemotherapy, endocrine therapy and, in some instances, CDK4/6 inhibitors.

The primary endpoint of Destiny-Breast06 was PFS in the HER2-low population, defined as having an IHC score of 1+, or IHC2+ with a negative in-situ hybridisation score (ISH-). Among the 713 patients in this group median PFS came in at 13.2 months, 5.1 months higher than for chemo, with a 0.62 hazard ratio; the numerical benefit was identical in all-comers.

Among the trial’s 152 ultralow patients, defined as IHC 0 with membrane staining, the mPFS numbers were nearly the same, at 13.2 versus 8.3 months. Meanwhile, confirmed ORR was also evenly spread among HER2-low, HER2-ultralow and all-comer patients.

Dr Giuseppe Curigliano of the European Institute of Oncology, Destiny-Breast06’s lead author, said work would now be done to establish the minimum level of HER2 expression necessary to see a benefit with Enhertu. These data could come at September’s ESMO conference.

Summary of Destiny-Breast06 data

Source: ASCO.