Results of ‘dramatic’ study for AstraZeneca and drug Daiichi suggest new way to treat aggressive breast cancer

Twenty-four years ago, a drug called Herceptin changed the way doctors treat breast cancer. Its approval in 1998 made it possible to target aggressive breast tumors linked to a gene called HER2. Other drugs soon followed Herceptin and over the years have dramatically improved the survival of people with the disease.

A quarter of a century later, another change in treatment may be on the horizon. At the American Society of Clinical Oncology meeting, AstraZeneca and Daiichi Sankyo present results proving that, for the first time, a targeted drug can help patients with metastatic breast cancer whose tumors only express low levels of HER2.

Clinical trial data revealed at ASCO and published Sunday in the New England Journal of Medicine shows that the drug, Enhertu, cut the risk of cancer progression by half compared to chemotherapy and reduced the risk of death by 36 %.

“It’s really, really impressive,” said William Jacot, study investigator and medical oncologist at the Montpellier Cancer Institute. “I didn’t expect something so good to be achievable with HER2 breast cancer.”

Halle Moore, another researcher and director of medical breast oncology at the Cleveland Clinic’s Taussig Cancer Institute, said some patients saw even greater benefit. The survival figures, she added, are “extremely significant”.

There are, however, important caveats. Enhertu is associated with a type of lung scarring that may require careful monitoring to be detected and managed. In a few cases during the trial, this side effect resulted in death. The duration of follow-up is also relatively short, so it is not clear how long the benefits might last. It’s unclear exactly what level of HER2 expression is required for Enhertu to work, or how useful the drug might be for so-called triple-negative patients, who have particularly rapid disease.

Nevertheless, the results should change the treatment of breast cancer, according to experts interviewed by BioPharma Dive. HER2 expression has long been viewed in binary terms, with a patient being diagnosed as ‘positive’ or ‘negative’. Yet about half of patients with metastatic breast cancer fall somewhere in between, with tumors that have low but still detectable levels of the protein. These patients do not benefit from drugs like Herceptin and chemotherapy is the typical treatment for many.

Enhertu could become the first HER2-targeting drug available for these patients. It could also change the way breast cancer is categorized, making it important to know not just whether tumors are HER2-positive, but also the exact amount of protein they express.

“This is really going to dramatically change our standard of care,” said Nancy Lin, a medical oncologist specializing in breast cancer at the Dana-Farber Cancer Institute. “In general, anyone with metastatic disease will need to know their HER2 status” and whether it is defined as “positive, low, or none.”

Lin did not participate in the trial but is a researcher in another Enhertu study and consulted for AstraZeneca.

AstraZeneca and Daiichi, which first claimed success for the study in February but delayed presenting details, said they intended to submit the results to regulators as soon as possible. In low-rate expressers, the Food and Drug Administration has already granted the drug Breakthrough Therapy Designation, a regulatory tool used to expedite reviews.

Improving prospects

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 tumours. This discovery led, in hesitant steps through academic centers and biotech company Genentech, to the drug that would become Herceptin.

The results of the first trials of Herceptin in breast cancer were so striking that they sparked protests from patients demanding faster access. A follow-up study confirmed a powerful benefit, and the FDA approved Herceptin soon after, establishing “HER2-positive” as a treatable type of breast cancer. Drugmakers, including Genentech’s eventual owner Roche, have been developing successor drugs like Perjeta and Kadcyla.

As is usually the case with cancer drugs, these HER2-targeting treatments were initially approved for advanced disease before being used earlier. Over time, the prognosis has 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 also improved, due to the emergence of multiple targeted therapies.)

“It used to be one of the worst prognostic types of breast cancer,” said Moore of the Cleveland Clinic. “Herceptin has been a game changer.”

A wise bet

Yet HER2 tumors can develop drug resistance, 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 drug that chemically binds a targeting antibody to a toxic payload. It was discovered by Japanese drugmaker Daiichi and proved so promising that AstraZeneca in 2019 paid nearly $7 billion to acquire partial rights.

AstraZeneca’s bet is now paying off. Months after the 2019 agreement, the drug was conditionally approved as a third-line treatment for the HER2-positive disease. Enhertu has since passed two more late-stage breast cancer trials, including one in which he beat Kadcyla.

Last month, Enhertu was also cleared for second-line use, bolstering analysts’ predictions that the drug will generate more than $4 billion in annual sales in 2026. Global sales outside of Japan totaled $426 million. dollars last year, of which AstraZeneca recorded $214 million in revenue. .

Enhertu’s potential as a first treatment for low HER2 disease is a big part of these projections, which is why investors are paying close attention to study details published at ASCO.

The trial randomized 557 patients with low HER2 expression who had previously received one or two lines of chemotherapy. Nearly 89% had HR positive disease, while the remaining 11% were HR negative. Patients received either Enhertu or “doctor’s choice” from one of five different chemotherapies.

The main aim of the study was to show that Enhertu could slow cancer progression compared with chemotherapy in HR-positive patients. Secondary measures assessed survival in HR-positive patients as well as all participants, and disease progression in the group as a whole. Enhertu achieved every goal, with an effect size that Dana-Farber’s Lin described as “quite dramatic”.

After a year and a half of follow-up, the researchers found that Enhertu had tumor control for a median of 10.1 months among those whose cancers were HR-positive, about twice as long as another cycle of chemotherapy.

These HR-positive patients lived on average just under two years compared to about 18 months for those who received chemotherapy.

HR-negative patients also benefited from the treatment, going an average 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 chemotherapy, with overall survival in the first group reaching a median of 18.2 months compared to 8.3 months in the second. Benefits of similar size were also reported in the overall study population.

However, the drug can be difficult to take. Before prescribing Enhertu, Lin tells patients that it “feels like chemotherapy,” with similar side effects like hair loss, nausea, and blood count issues. Although serious side effects were more common with chemotherapy than with Enhertu, drug-related lung scarring, known as interstitial lung disease, or pneumonitis, occurred in approximately 12% of patients treated with Enhertu and resulted in were fatal for three of them. A patient on chemo had pulmonary side effects.

The drug’s safety profile means doctors should be careful prescribing it to people with serious underlying lung disease, Moore said. “We have to be careful, of course,” added Jacot.

But he, Lin and Moore felt that the obvious benefits of Enhertu are worth discussing and expect the drug to be widely used. Doctors are also getting better at quickly identifying and managing the pulmonary side effect, Lin said.

Now they will have to figure out who is “HER2 low,” what ASCO breast cancer expert Jane Lowe Meisel called in a statement a “new category of breast cancer” because of the study results. .

“We need to create a new ranking,” Jacot said. “We clearly need to make everyone believe that low HER2 is something different.”

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