With new Enhertu data, an ADC could overtake chemo in breast cancer
4 min read
Two years ago, a drug called Enhertu changed the way doctors thought about treating an aggressive form of breast cancer, making it important to know not only whether their patients’ tumors express a protein known as HER2, but how much.
New study results presented Sunday at the American Society of Clinical Oncology may further shift breast cancer care. The findings suggest Enhertu, a type of medicine called an antibody-drug conjugate, should be used before chemotherapy in a common type of advanced breast cancer. They may also usher in a new classification for breast tumors — those with “ultralow,” but still detectable, levels of HER2 protein.
The trial tested Enhertu against doctor’s choice of chemotherapy in 866 people with metastatic, hormone receptor-positive breast tumors that had either “low” or “ultralow” HER2 expression. Study participants had already received one hormone therapy and a type of drug called a CDK 4/6 inhibitor, or at least two prior hormone therapies.
Enhertu’s developers, AstraZeneca and Daiichi Sankyo, said in April the trial succeeded, but didn’t provide specifics. Trial data revealed at ASCO show Enhertu met its main objective by delaying cancer progression or death by a median of about 13 months, versus roughly eight months for those who received chemotherapy. That result translated to a 38% reduction in the risk of cancer progression for people who got Enhertu.
“That’s an attention-grabbing difference,” said Adrienne Waks, the associate director of breast oncology clinical research at Dana-Farber Cancer Institute. Waks wasn’t involved with the trial, but has served as an adviser for AstraZeneca.
Nearly identical results were observed in the smaller group of people with ultralow HER2 levels, equating to a similar five-month difference versus chemo in so-called progression-free survival. Though the study wasn’t powered to detect a statistical difference on that measure, experts interviewed by BioPharma Dive still say the finding is convincing.
“This data, in addition to data from other studies, do suggest that this population is likely to benefit,” added Rachel Layman, a breast medical oncologist at The University of Texas MD Anderson Cancer Center. Layman also didn’t take part in the trial, but is an investigator in a different Enhertu study.
There are some caveats. The study hasn’t continued for long enough to clearly tell whether Enhertu extends survival. Enhertu was also associated with higher rates of serious drug-related side effects, among them a type of lung scarring — interstitial lung disease — that can require rigorous monitoring to detect and manage. While this side effect wasn’t serious for most patients who received Enhertu, about 5% stopped treatment because of it and three died.
Interstitial lung disease is the “biggest downside” of Enhertu and “gives me pause” before prescribing, Layman said.
Waks, of Dana-Farber, added that doctors should carefully choose who to treat with Enhertu. An oft-prescribed chemotherapy called capecitabine is administered orally, unlike the intravenously infused Enhertu, and that drug isn’t associated with lung scarring or hair loss, the latter of which is also a concern for patients, she said.
While the efficacy reported is “quite impressive,” Waks said, “it is problematic to just say, based on these results, we’re going to move this agent into the first line for every eligible patient.”
According to estimates from AstraZeneca, as many as two-thirds of hormone receptor-positive breast cancers typically classified as negative for HER2 expression actually have low levels of the protein. The company says another 20% to 25% may have “ultralow” HER2 expression.
Hormone therapies and CDK4/6 drugs are widely used to treat those patients first. If their cancers progress, people typically move on to chemotherapy, with limited benefits. Enhertu is currently only available after chemo.
AstraZeneca and Daiichi have been trying to show the drug can be given earlier, part of a plan to make antibody-drug conjugates, or ADCs, a mainstay in cancer care. ADCs are designed to deliver toxins more precisely to tumors than traditional chemo, a sort of “next-generation chemotherapy,” Layman says. After decades of research, they’ve recently come of age, catalyzing billions of dollars in deals and investments by pharmaceutical and biotechnology companies.
AstraZeneca and Daiichi, through two ADC-focused collaborations, have made these drugs a priority. In a recent presentation, for example, AstraZeneca executives discussed the potential for ADCs to supplant chemotherapy in many tumor types, starting with Enhertu in breast cancer and eventually moving to others.
“The key goal from this trial is to show the power of ADCs in truly replacing chemotherapy,” said Mohit Manrao, the senior vice president of AstraZeneca’s U.S. oncology division, in an interview. “We are seeing with this therapy, we can displace traditional chemotherapy and bring it earlier to the patients.”
AstraZeneca has already said it intends to share the trial’s results with regulators. Even if a new approval is forthcoming, though, some experts anticipate challenges in identifying people with ultralow HER2 expression. Already, clinicians are dealing with a learning curve following the 2022 clearance of Enhertu in HER2-low breast cancer. That approval forced doctors to think of HER2 expression beyond binary positive or negative terms, and made it important for pathologists to correctly identify low status in tumor samples.
According to Layman, the lab technique used to make those judgments is somewhat subjective, meaning each pathologist might report a different result from the same sample. Adding an ultralow category adds another wrinkle that may be harder for some pathologists — particularly those in community oncology centers — to iron out, she said.
“This is a new category,” Layman said. “I think there are concerns about the applicability to the country as a whole.”
