A new era of breast cancer treatment could be upon us.
With a landmark clinical trial win, AstraZeneca and Daiichi Sankyo could soon open up a brand-new breast cancer category and offer HER2-targeted therapy for many patients with what’s been traditionally characterized as HER2-negative disease.
That’s all thanks to data from the phase 3 Destiny-Breast04 study. It showed that the companies’ Enhertu reduced the risk of disease progression or death by a whopping 50% and the risk of death by 36% in a group of patients with previously treated HER2-low metastatic breast cancer.
At a median follow-up of 18.4 months, Enhertu extended the median time patients had lived without disease worsening to 9.9 months, versus 5.1 months for patients who got physician’s choice of chemotherapy. The drug prolonged patients’ lives to a median of 23.4 months, compared with 16.8 months for chemo.
The data presentation, made by Shanu Modi, M.D., at Memorial Sloan Kettering Cancer Center, received a long-lasting standing ovation during a plenary session of the 2022 American Society of Clinical Oncology annual meeting. The data are simultaneously published in The New England Journal of Medicine.
The results are “phenomenally spectacular,” Ken Takeshita, M.D., global head of R&D at Daiichi Sankyo, said in an interview with Fierce Pharma.
Based on the data, SVB Securities analyst Andrew Berens, M.D., projected in a Monday note that Enhertu could reach $4.6 billion sales in HER2-low patients alone by 2030.
HER2 expression is determined by two tests, one called an immunohistochemical (IHC) analysis that measures the amount of HER2 protein on cancer cells, and the other called in situ hybridization (ISH), which is used to detect genetic materials. Traditionally, tumors with IHC of at least 3, or IHC 2 accompanied by a positive ISH test, are labeled HER2-positive, and patients typically receive a HER2 drug. But now, Enhertu is trying to carve out those with IHC 1+ or IHC 2+ with a negative ISH score and call them HER2-low.
The Destiny-Breast04 readout represents a “pivotal moment” because for the first time, a HER2-directed therapy has identified the patient population of HER2-low, including disease that's hormone receptor-positive and -negative, which covers about half of all breast cancer patients—and has shown impressive efficacy, Susan Galbraith, Ph.D., AZ’s oncology R&D lead, said in a separate interview.
“By effectively creating a new category of breast cancer, HER2-low, this trial will redefine how we classify breast cancer and will significantly expand the population of patients who can benefit from HER2-targeted therapy,” Jane Lowe Meisel, M.D., a breast cancer expert with Emory University, said in a statement on behalf of ASCO.
Consistent results across patient subgroups
As a trailblazing study, people naturally want to understand whether all patients under this new HER2-low category could benefit from Enhertu. The drug didn’t disappoint, showing consistent results across all subgroups tested.
In patients with HR-positive disease, which constitutes the trial’s primary endpoint analysis, Enhertu cut the risk of disease progression or death by 49%. The drug nearly doubled the median progression-free survival (PFS) to 10.1 months, versus 5.4 months for chemo.
Among those with HR-negative disease, the size of the risk reduction on progression-free survival was similar at 54%. The median PFS between Enhertu and chemo were 8.5 months and 2.9 months, respectively.
Within the HR-positive group, in patients who had received prior treatment with a CDK4/6 inhibitor, the progression-free risk reduction was 45%. For about a quarter of the trial population who had no prior CDK4/6 experience, that number was 58%.
Perhaps more importantly, Enhertu showed similar results in IHC 1+ and IHC 2+ subgroups, cutting the PFS risk by 52% and 45%, respectively, among HR-positive patients.
|Enhertu median PFS||Chemo median PFS||Risk reduction|
|HR+||10.1 months||5.4 months||49%|
|HR-||8.5 months||2.9 months||54%|
|Prior CDK4/6||10 months||5.4 months||45%|
|No prior CDK4/6||11.7 months||5.9 months||58%|
|IHC 2+/ISH-||10.1 months||5.9 months||45%|
|IHC 1+||10.3 months||5.3 months||52%|
The fact that Enhertu showed a strong improvement even in those at the lower end of HER2-low expression “raises the question about whether there’s a HER2-ultralow population, if you like, that will also benefit,” AZ’s Galbraith said.
As Daiichi’s Takeshita noted, the lower end of the IHC 1+ cutoff is a faint staining suggesting HER2 expression in 10% of tumor cells. It raises the question, wouldn't patients with a 9.9% result—and thus grouped as IHC 0—benefit from Enhertu? Or, how low can the HER2 expression be for Enhertu to work?
Daiichi and AZ aim to find out, Takeshita and Galbraith said. The first clues could come from the ongoing Destiny-Breast06 trial, which is testing Enhertu in an earlier line of treatment right after disease progression on endocrine therapy in metastatic patients. In Destiny-Breast04, patients had also received one prior chemotherapy.
En route to changing clinical practice
But before that, the companies will discuss the current data with regulatory authorities, including the FDA, about potential approvals. There could be one uncertainty in that endeavor. In the 557-patient Destiny-Breast04 trial, HR-negative patients only represent 11.3% of the total. So it’s possible that the FDA may think the data aren’t enough for that patient subgroup and therefore limit an approval to HR-positive patients.
The companies included the HR-negative population in Destiny-Breast04 at the recommendation of drug regulators, Galbraith said. For this indication, Enhertu has an FDA breakthrough therapy designation, she noted, which means more intensive FDA guidance on an efficient drug development program.
“When you think about the context, the unmet need and the quality of the data that we’ve seen and consistency across different groups,” the pair looks forward to having a conversation with the FDA to potentially get Enhertu approved for the patient population enrolled in Destiny-Breast04, Galbraith said.
Beyond efficacy, Enhertu has also been linked to a potentially dangerous side effect known as interstitial lung disease (ILD), which causes scarring of the lungs. In Destiny-Breast04, 45 Enhertu patients (12.1%) experienced drug-related interstitial lung disease, according to an independent review committee, including 3 (0.8%) deaths. By comparison, only 1 patient in the chemo arm experienced a low, grade 1 case of the lung problem.
The death rate was lower than the 2.6% seen in the Destiny-Breast01 trial, which got Enhertu its original FDA approval as a third-line therapy for HER2-positive patients.
Daiichi and AZ see less serious ILD events for Enhertu as they test the drug in more clinical trials and in earlier disease settings, Takeshita said. That’s probably because the pair has developed better ways to detect and manage the side effects, and because patients earlier in their disease course have received fewer previous treatments that may already have done damage to the pulmonary system, he explained.
Still, industry watchers have argued that Enhertu needs to get the ILD problem under control to achieve meaningful market penetration in earlier treatment lines, where effective drugs are already available.
If approved, Enhertu will be the first targeted drug under this new concept of HER2-low. So even though the HER2 tests are readily available, Galbraith said she expects education is needed to actually change clinical practice.
As Galbraith sees it, Enhertu’s success in HER2-low breast cancer “represents the potential opportunity for this technology of antibody-drug conjugates to replace current chemotherapy in different settings.”
Editor's Note: The story has been updated with a description of the standing ovation, a sales projection from SVB Securities and new PFS numbers for the HR-negative subgroup.