Bispecific Cancer Drug Performs Well in Early Clinical Trial

An international, early-phase clinical trial, led by UPMC Hillman Cancer Center scientists, reported that a “two-for-one” cancer immunotherapy is potentially more effective and at least as safe as standard immunotherapies. Recently published in Nature Medicine, the findings, which involved hundreds of patients with different types of advanced solid tumors or blood cancers, point to an enticing new path for bispecific therapies that more efficiently unleash the patient’s own immune system to combat cancer.

“No approved cancer drugs are like this. It is truly a novel development in the field,” said lead author Jason Luke, MD, director of the Immunotherapy and Drug Development Center at UPMC Hillman and associate professor of hematology and oncology at the University of Pittsburgh School of Medicine. “The patients in our trial had cancers that were not responding to other therapies, so to see double-digit response rates is encouraging.”

Tebotelimab: The bispecific drug

Some cancers proliferate when the patient’s immune system stops fighting them—in some cases because the cancer itself is turning off the immune response. Tebotelimab, the drug used in the trial, is a checkpoint inhibitor. Usually, checkpoint inhibitor drugs target one immune system protein, but tebotelimab is bispecific and blocks two proteins: PD-1 and LAG-3.

Drugs that block PD-1, such as pembrolizumab or nivolumab, have become the focus of treatment for many types of cancer. LAG-3-blocking drugs have recently been approved for advanced melanoma, but little clinical data exist to date for the treatment of other types of cancer.

Luke says one drug doing the work of two may be better than two separate drugs, which might engage the immune system differently. When two drugs are used, they may not specifically bind together on the same immune cells. When one bispecific drug with two immune molecules binds to immune cells, the interactions are different and potentially generate greater immune activation. In addition, the bispecific drug is not more toxic to the patient than one monospecific drug, whereas giving a patient two monospecific drugs typically would have added side effects.

Effect on HER2-positive cancers

The team enrolled 269 patients with advanced disease, including types of ovarian, breast, head and neck, cervical, and lymphoma cancers. Tumor size decreased in 34 percent of eligible participants posttreatment.

The research team took the trial a step further and enrolled another 84 patients with advanced HER2-positive cancers to test tebotelimab combined with an approved drug for HER2-positive cancer, called margetuximab. The response rate in those participants was 19 percent, which Luke said was impressive given the response rate is usually closer to 0 percent.

Luke says the next step is to develop a biomarker test that will inform clinicians which patients have cancers that are expressing the proteins that tebotelimab is designed to block and then conduct another trial to see if outcomes further improve. Additionally, future trials could test immunotherapy in combination with chemotherapy or radiation.

“The early suggestion of response across multiple cancer types is intriguing,” said Luke. “This deserves further study, especially since this early phase trial gave us much more certainty around the safety of tebotelimab.”

- This press release is supported by the University of Pittsburgh