Twenty-four years ago, a drug called Herceptin changed how doctors treat breast cancer. Its approval in 1998 made it possible to target the aggressive breast tumors tied to a gene called HER2. Other drugs quickly followed Herceptin and, over the years since, have substantially improved survival for people with the disease.
A quarter of a century later, another shift in treatment could be on the horizon. At the American Society of Clinical Oncology meeting, AstraZeneca and Daiichi Sankyo are presenting results proving that, for the first time, a targeted medicine can help metastatic breast cancer patients whose tumors express only low levels of HER2.
Clinical trial data revealed at ASCO and published in The New England Journal of Medicine Sunday show the drug, Enhertu, halved the risk of cancer progression compared to chemotherapy and reduced the risk of death by 36%.
“This is really, really impressive,” said William Jacot, a study investigator and medical oncologist at the Montpellier Cancer Institute. “I was not expecting something near so good to be achievable with HER2 breast cancer.”
Halle Moore, another investigator and the director of breast medical oncology at the Cleveland Clinic’s Taussig Cancer Institute, said some patients achieved an even greater benefit. The survival numbers, she added, are “extremely meaningful.”
There are important caveats, however. Enhertu is associated with a type of lung scarring that can require stringent monitoring to detect and manage. In a few cases in the trial, this side effect led to death. The length of follow-up is also relatively short, so it’s unclear just how long benefits might endure. It’s unknown exactly what level of HER2 expression is required for Enhertu to work, or how helpful the drug might be for so-called triple-negative patients, who have particularly fast-moving disease.
Nonetheless, the results are expected to change breast cancer treatment, according to experts interviewed by BioPharma Dive. HER2 expression has long been considered in binary terms, with a patient diagnosed as either “positive” or “negative.” Yet about half of metastatic breast cancer patients are somewhere in between, with tumors that have low, but still detectable levels of the protein. These patients don’t benefit from drugs like Herceptin and chemotherapy is the typical treatment for many.
Enhertu could become the first HER2-targeting medicine available to these patients. It could also shift how breast cancer is categorized, making it important to know not only whether tumors are HER2-positive, but exactly how much protein they express.
“It's going to really significantly change our standard of care,” said Nancy Lin, a medical oncologist specializing in breast cancer at the Dana-Farber Cancer Institute. “In general, everyone who has metastatic disease is going to need to know their HER2 status,” and whether it’s defined as “positive, low, or zero.”
Lin wasn’t involved with the trial but is an investigator in a different Enhertu study and has consulted for AstraZeneca.
AstraZeneca and Daiichi, which first claimed study success in February but held off presenting details, have said they intend to submit the results to regulators as soon as possible. In low expressers, the Food and Drug Administration has already granted the drug a Breakthrough Therapy designation, a regulatory tool that is used to speed up reviews.
The HER2 gene was first discovered and linked to breast cancer in the 1980s, when the protein it expressed was found in high levels on certain tumors. That finding led, in halting steps at academic centers and at the biotech company Genentech, to the drug that would become Herceptin.
Results from early breast cancer trials of Herceptin were so striking they sparked patient protests demanding faster access. Follow-up study confirmed a powerful benefit and the FDA approved Herceptin soon after, establishing “HER2-positive” as a treatable breast cancer type. Drugmakers, including Genentech’s eventual owner Roche, developed successor medicines like Perjeta and Kadcyla.
As is typical of cancer drugs, these HER2-targeting treatments were initially approved for advanced disease before they were used earlier. Over time, the prognosis improved for people with HER2-positive tumors, which are historically associated with higher rates of relapse and death and are more likely to spread to the brain. (The outlook for those whose tumors are classified as HER2-negative has improved as well, due to the emergence of multiple targeted treatments.)
“It used to be one of the worst prognostic types of breast cancer,” said Moore, of the Cleveland Clinic. “Herceptin was a game-changer.”
A shrewd bet
Still, HER2 tumors can develop resistance to drugs, creating a need for better treatments. Enhertu is the latest in a growing list of them. Like Roche’s Kadcyla, Enhertu is an antibody-drug conjugate, a medicine that chemically links a targeting antibody to a toxic payload. It was discovered by the Japanese drugmaker Daiichi and showed so much early promise that AstraZeneca in 2019 paid nearly $7 billion to acquire partial rights.
AstraZeneca’s gamble is now paying off. Months after the 2019 deal, the drug was conditionally approved as a third-line treatment for HER2-positive disease. Enhertu has since succeeded in two additional late-stage breast cancer trials, including one in which it bested Kadcyla.
Last month, Enhertu was cleared for second-line use as well, bolstering analyst predictions the drug will generate more than $4 billion in yearly sales in 2026. Global sales outside of Japan totaled $426 million last year, from which AstraZeneca recorded $214 million in revenue.
Enhertu’s potential as the first treatment for low-HER2 disease is a big part of those projections, which is why investors are paying close attention to the study details released at ASCO.
The trial randomized 557 patients with low expression of HER2 and who had previously received one or two lines of chemotherapy. Nearly 89% had HR-positive disease, while the remaining 11% were HR-negative. Patients were given either Enhertu or “physician’s choice” of one of five different chemotherapies.
The study’s main goal was to show Enhertu could slow cancer progression compared to chemotherapy in HR-positive patients. Secondary measures assessed survival in HR-positive patients as well as in all participants, and disease progression in the overall group. Enhertu met each goal, with an effect size that Dana-Farber’s Lin described as “quite dramatic.”
After a year and a half of follow-up, researchers found Enhertu had held tumors in check for a median of 10.1 months among those whose cancers were HR-positive, roughly twice as long as another round of chemotherapy.
These HR-positive patients lived a median of just under two years versus about 18 months for those given chemo.
HR-negative patients also benefited from treatment, going a median of 8.5 months without their tumors growing compared to 2.9 months for the chemotherapy group. They lived about 10 months longer than those on chemo, with overall survival in the former group reaching a median of 18.2 months compared to 8.3 months in the latter. Similar-sized benefits were reported in the overall study population as well.
However, the drug can be difficult to take. Before prescribing Enhertu, Lin tells patients it “feels like chemotherapy,” with similar side effects like hair loss, nausea and blood count issues. Though severe side effects were more common with chemotherapy than Enhertu, drug-related lung scarring known as interstitial lung disease, or pneumonitis occurred in about 12% of Enhertu-treated patients and was fatal for three of them. One patient on chemo had lung side effects.
The drug’s safety profile means physicians should be careful prescribing to those with severe underlying lung disease, Moore said. “We need to be cautious, for sure,” Jacot added.
But he, Lin and Moore felt Enhertu’s clear benefits make treatment worthwhile and expect the drug will be widely used. Doctors are getting better at quickly identifying and managing the lung side effect, too, Lin said.
Now they’ll need to figure out who is “HER2 low,” something ASCO breast cancer expert Jane Lowe Meisel called in a statement a “new category in breast cancer” because of the study results.
“We need to create a new classification,” said Jacot. “We clearly need to make everybody think that HER2 low is something different.”