ASCO: AstraZeneca, Daiichi's Enhertu looks to make history again in HER2-ultralow breast cancer

After Enhertu pioneered the HER2-low category in breast cancer treatment, AstraZeneca and Daiichi Sankyo are now hopeful that the antibody-drug conjugate can reach tumors with an even lower expression of the protein biomarker.

In a group of patients with previously treated, HR-positive metastatic breast cancer with low levels of HER2 expression, Enhertu significantly cut the risk of disease progression or death by 37% versus a physician’s choice of chemotherapy, according to results from the DESTINY-Breast06 trial shared Sunday at the American Society of Clinical Oncology annual meeting in Chicago.

Compared with the DESTINY-Breast04 trial that scored Enhertu its landmark FDA approval in HER2-low breast cancer in 2022, DESTINY-Breast06 didn’t include patients with HR-negative disease. Instead, it moved treatment into an earlier line prior to the use of chemotherapy.

More importantly, the new study enrolled patients with even lower levels of HER2 expression and described them as being in the "HER2-ultralow" category.

Lower HER2 expression

HER2 expression is typically determined by an imaging diagnostic method called immunohistochemistry (IHC), which uses immunochemical staining of tissues to visualize the presence of target biomarkers. For patient categorization purposes, the HER2-low category includes those with a minimum HER2 expression at an IHC score of 1+, or faint membrane staining in at least 10% of tumor cells.

With the HER2-ultralow group, AZ and Daiichi are pushing the boundary into IHC 0 and are keeping the requirement for faint membrane staining.

Of all traditional HR-positive, HER2-negative metastatic breast cancer cases, about 60% to 65% are considered HER2-low. Around 20% to 25% fit the HER2-ultralow definition.

A subgroup analysis of 152 HER2-ultralow patients enrolled in DESTINY-Breast06 found that Enhertu cut the risk of disease progression or death by 22% versus chemo. The number didn't bear statistical significance. The median progression-free survival (PFS) was 13.2 months for Enhertu and 8.3 months for chemo in the ultralow group.

On the trial’s primary endpoint, which focuses on PFS in the HER2-low group, Enhertu’s risk reduction was statistically significant at 38%. In this subgroup, patients who received Enhertu went 5.1 months longer without progression than those in the control group did, reaching a median of 13.2 months.

Overall survival data remained immature. After a median follow-up of 18.6 months, Enhertu showed a preliminary 17% favorable trend toward improved survival in HER2-low patients, or 25% in HER2-ultralow disease.

AstraZeneca’s oncology R&D chief Susan Galbraith, Ph.D., characterized Enhertu’s performance in HER2-low and HER2-ultralow subgroups as “exciting.” And Daiichi Sankyo’s head of global oncology development, Mark Rutstein, M.D., said the latest data gave the company confidence that Enhertu can continue to “reclassify the treatment of breast cancer.”

The magnitude of the drug’s PFS benefit was expectedly smaller in the HER2-ultralow group than the HER2-low group. Its benefit also pales in comparison to the massive 50% PFS improvement and the significant 36% death reduction that earned Enerhtu’s DESTINY-Breast04 results a standing ovation at the ASCO 2022 meeting.  

During a Saturday press briefing, Erica Mayer, M.D., a Dana-Farber Cancer Institute breast cancer expert invited by ASCO, said the new DESTINY-Breast06 results are exciting as they could allow doctors to potentially move Enhertu into earlier treatment for a larger population.

“However, as was outlined, there are specific toxicities associated with this agent that may be more significant compared to traditional chemotherapy in this setting,” Mayer added. “Therefore, this is a change that we will bring back to our clinics, and we will discuss with patients. This will not be for every patient.”

She was likely referring to the three (0.7%) Enhertu takers who died of drug-related interstitial lung disease (ILD). Altogether, 49 patients (11.3%) in the Enhertu group had adjudicated ILD, most of which were grade 1 or 2, whereas the control group only recorded one (0.2%) grade 2 event.

ILD is a known problem for Enhertu and Daiichi’s DXd ADC technology. In DESTINY-Breast04, the rate of ILD linked to Enhertu was 12.1%, including a 0.8% rate of deaths.

One factor that doesn’t bode well for Enhertu from the two HER2-low trials is a signal of shrinking treatment effect as the ADC pushes into an earlier treatment setting. The PFS benefit was 50% for Enhertu against standard of care in post-chemo HER2-low treatment and now 38% in the pre-chemo setting.

As analysts have pointed out, Enhertu will need a big treatment effect in the first-line setting to compensate for its ILD problem, especially as CDK4/6 inhibitors and endocrine therapies have shown great efficacy under the traditional HR-positive, HER2-negative patient categorization.

Susan Galbraith
Susan Galbraith, Ph.D. (AstraZeneca)

AZ and Daiichi have not yet unveiled their front-line strategy for Enhertu in HER2-low breast cancer. But AZ’s Galbraith hinted at the possibility of a more careful selection of patients for future research. 

“There’s variation in how well that class of agents works across the ER-positive group,” Galbraith said of the CDK4/6 inhibitors. “So, I think there’s discussion about other segments within that group where there’s potential for benefit from Enhertu. But those are trial designs that are works in progress.”

Identifying the right patients

When DESTINY-Breast04 data were first presented at the ASCO 2022 meeting, researchers and doctors flagged another problem for the rollout of a HER2-low indication: the proper identification of patients.

At that time, pathologists were expected to have a hard time accurately distinguishing IHC 1+ from IHC 0, the latter of which would make a patient ineligible for Enhertu under the HER2-low indication.

Now, with DESTINY-Breast06, AZ and Daiichi are trying to further break up the IHC 0 category into HER2-ultralow and HER2-null.

“I think we’ll need a lot of discussion with our pathology colleagues on that HER2-ultralow in particular, and the reliability of just seeing a little bit of faint membrane staining versus not,” ASCO Chief Medical Officer Julie Gralow, M.D., a breast cancer expert previously with the Fred Hutchinson Cancer Center, said while leading Saturday’s press conference.

“I don’t know if our eyes are good enough to see that difference. I don’t know if our stains are good enough to see that difference. And that’s where we’re going to work with our pathology colleagues because we might not have a good discriminator when it’s that low,” Gralow said later during the briefing.

Aditya Bardia, M.D., an investigator of DESTINY-Breast06, also agreed that the HER2 IHC was not designed to distinguish HER2 expression at this low level. But he argued that Enhertu could work as long as there is abnormal HER2 expression.

AstraZeneca’s Galbraith, in an interview with Fierce Pharma, argued that the differentiation between HER2-ultralow and HER2-null may be as simple as spotting any level of brown staining on the image. By comparison, telling HER2-low apart from HER2-ultralow requires a determination in the size of staining.

In his separate interview with Fierce Pharma, Daiichi’s Rutstein said picking up a faint expression versus complete absence would be “fairly dichotomous.” He also suggested that, if the FDA approves the HER2-ultralow indication, proper training could help practitioners classify patients.

“We’re confident with what we’ve done in DESTINY-Breast04 HER2-low, we think that with the tools that we use there to be deployed here, we will, if given the opportunity, with regulatory approval, we will be able to get the job done making sure these patients are appropriately re-stratified and identified,” Rutstein said.