Wedged into the surface of a tumor cell, the protein called HER2 acts as a homing beacon for some of the most potent cancer medicines developed. Its discovery decades ago, and abnormal abundance in some breast cancers, led to the development of targeted drugs like Herceptin that have greatly improved patient care.
Results from an exploratory clinical trial unveiled Monday suggest targeting HER2 could also be a useful strategy against other cancers that are not as widely associated with the protein.
The findings, which will be presented at the American Society of Clinical Oncology’s annual meeting in Chicago, show that a newer HER2-targeting drug called Enhertu shrank tumors of the uterus, cervix, ovaries, bladder and, to a lesser extent, bile duct. In this way, they’re another data point in a yearslong shift toward describing cancers by their genetics, rather than only by their location in the body.
Developed by AstraZeneca and Daiichi Sankyo, Enhertu is different from drugs like Herceptin, which interfere with how HER2 incites tumor growth. Instead, Enhertu combines a targeting molecule aimed at HER2 with a cell-killing toxin in a biochemical assemblage known as an antibody-drug conjugate.
“The reason why this [result] is exciting is that the tumor doesn't have to be addicted to HER2 to respond to this therapy,” said Angela DeMichele, a medical oncologist at Penn Medicine. “The HER2 in this case is acting as a docking station for delivery of the chemotherapy.”
“It’s almost like a proof of concept that we can get benefit from these drugs, these antibody-drug conjugates, even when what the antibody is binding to is not what is driving the tumor,” added DeMichele, who was not involved in the study.
Enhertu is already approved in the U.S. to treat HER2-positive and HER2-low breast cancer, as well as HER2-positive gastric and lung cancers. It has proven a powerful option for those types of tumors, and in the process recast how doctors think of HER2 status for breast cancer.
Monday’s results point in new directions. AstraZeneca and Daiichi’s study is what’s known as a “basket” trial, enrolling patients with a range of cancers meeting certain criteria and testing a targeted therapy against them. In this case, participants had locally advanced or metastatic solid tumors that were positive for HER2 and had received at least one prior systemic treatment.
Among trial volunteers whose tumors had the highest HER2 expression, researchers reported that more than 50% of those with endometrial, cervical, ovarian, urothelial or biliary tract cancer responded to Enhertu. Response rates, which reflect reduction in tumor size, were lower when participants with less HER2 expression were included, ranging from 22% overall in biliary tract cancer to nearly 58% in endometrial cancer.
“We think this is really exciting data,” said Funda Meric-Bernstam, chair of the University of Texas MD Anderson Cancer Center’s investigational cancer therapeutics department and the study’s lead investigator.
Meric-Bernstam noted how, across all study participants, responses to Enhertu lasted a median of nearly one year. However, in those with the highest HER2 expression the median duration of response doubled to 22 months — a finding she described as “compelling.”
Across all 267 people in the trial, the rate of response was 37%, in part reflecting how few patients with pancreatic cancer had their tumors shrink after Enhertu treatment.
“The pancreatic [data are] a disappointment, but it has to do with the fact that there’s just not a lot of HER2 on the surface,” said DeMichele, who hypothesized that less drug might have reached the tumor. DeMichele reviewed the data for BioPharma Dive ahead of its release on the condition she not share it.
The data are interim findings, and don’t describe measures like how long patients went without their disease progressing, or how long they lived following treatment.
Like all cancer drugs, Enhertu comes with side effects, including a type of lung inflammation called pneumonitis that can be dangerous. Of the 18 participants who were diagnosed with it, 17 had asymptomatic or treatable symptoms, but one died. The risk is treatable, said DeMichele. “but it’s going to be a limit.”
Enhertu was also associated with nausea, fatigue and low levels of blood cells.
Mohit Manrao, a senior vice president with AstraZeneca’s U.S. oncology business unit, said the data “open up avenues” for bringing Enhertu to patients with different HER2-expressing cancers.
“This data will support our ongoing conversations with regulatory authorities,” Manrao said. “This was a Phase 2b study, so depending on [those] conversations the next steps would be informed from there.”
One takeaway from the study’s findings, if borne out in further research, could be encouraging wider testing of HER2 expression in cancers beyond breast and gastric.
“The fact that we're seeing such clinically meaningful activity, one could argue that, across tumor types that are epithelial, we should consider HER2 testing,” said Meric-Bernstam.
“We all need to become biomarker experts now,” said DeMichele, “because we need to understand the biomarker profile of our patients’ tumors and how they change over time.”