Enhertu approved for solid cancers with HER2

June 14, 2024by Carmen Phillips

The drug trastuzumab deruxtecan (Enhertu) can now be used to treat a wide variety of cancers, thanks to new approval by the Food and Drug Administration (FDA).

On August 5, the FDA granted accelerated approval for the use of trastuzumab deruxtecan (commonly called T-DXd) to treat people with any advanced solid cancer whose tumors produce high levels of the HER2 protein. Those who had at least one previous treatment will be able to receive the medication.

The approval makes T-DXd the first antibody-drug conjugate treatment to be used in such a “tumor type-independent” manner. T-DXd is already approved to treat several types of cancer in people, including breast and stomach cancer.

The new approval was based on the results of three medium-sized clinical studies in which treatment with T-DXd shrank tumors (a tumor response) in many people with advanced HER2-positive cancers. In many cases, the tumors did not grow back for several months or years.

In approval, the FDA noted that T-DXd sometimes causes serious side effects, including a dangerous lung inflammation called interstitial lung disease (ILD). During the studies, some patients died from PID.

Oncologists will need to consider the possible side effects of T-DXd when considering whether to recommend it to patients, said Dr. Funda Meric-Bernstam of the University of Texas MD Anderson Cancer Center, who is the principal investigator of one of the three studies.

However, there is significant evidence of “compelling activity” in many different types of cancer, Dr. Meric-Bernstam continued. Based on these tests, she indicated that, “I hope there is great acceptance [del T-DXd]” by oncologists.

From breast cancer to clinical trials for a multitude of cancers

Trastuzumab (Herceptin), a type of drug known as a monoclonal antibody, was one of the first targeted cancer therapies to be approved by the FDA. It works by seeking out and attaching to HER2 proteins on cancer cells to prevent the protein from promoting tumor growth and to stimulate attack by immune cells.

In the case of T-DXd, trastuzumab works through a chemical bond with deruxtecan, a chemotherapy drug. Trastuzumab’s job in T-DXd is to be the driver that delivers the drug to the final destination: cells that have HER2 on the surface. After binding to HER2, the drug enters the cell whole and releases the payload, deruxtecan, to destroy the cell.

Trastuzumab was formulated in the 1990s to treat breast cancer in particular. This was because studies at the time had shown that the tumors in about 20% of people with breast cancer had cells with excess HER2 on the surface, called HER2 overexpression.

But over the past 10 to 15 years, scientists have found again and again that this HER2 overexpression appears in many other cancers. In that same period, the FDA approved numerous drugs targeting HER2, including T-DXd.

With compelling data and multiple treatments available, many clinical studies were launched to test different HER2-targeting therapies in people with cancers in whom HER2 overexpression is common. Among them were three Phase 2 studies of T-DXd, funded by AstraZeneca and Daiichi Sankyo (the drug’s manufacturer), on which this recent FDA approval was based.

Intense and often long-lasting responses to T-DXd in many cancer types

One of the three studies enrolled only people with advanced lung cancer, another enrolled only people with advanced colorectal cancer, and the last enrolled people with different types of advanced solid cancers.

All participants in all three studies had HER2-positive tumors. However, while most participants’ tumors had the highest HER2 concentrations (a measurement known as IHC3+), some had slightly lower concentrations (a measurement known as IHC2+).

In the study of different types of tumors (pantumor), more than half of people with IHC3+ tumors responded to treatment. Many of those tumor responses lasted 20 months or more, although others only lasted a few months.

The most impressive responses were seen in people with IHC3+ gynecologic cancers. For example, about 85% of people with endometrial cancer and 75% of people with cervical cancer responded to T-DXd. Many of these responses lasted at least 1 year and some lasted much longer.

Response rates were also high among participants with rare and difficult-to-treat cancers. For example, more than 56% of people with IHC3+ biliary system cancer had a response, some lasting almost 2 years.

Additionally, 42% of people with salivary gland cancer had a tumor response, including several lasting more than 20 months.

In studies of lung and colorectal cancer, tumors also shrank in about half of the patients. But those responses tended to last much shorter than those seen in other types of tumors.

Staying vigilant for interstitial lung disease

The most common side effects of T-DXd include nausea, anemia, and fatigue. In the pantumor study, about 30% of participants had their drug dose decreased or treatment stopped due to side effects.

In general, about 10% to 15% of people treated with T-DXd develop PID, the most common form of which is pneumonitis.

“Not all oncologists may be familiar with interstitial lung disease or pneumonitis, [y es] an important adverse event that we should be aware of,” explained Dr. Meric-Bernstam.

In most cases, PID is easy to treat when it occurs. But he cautioned that it is important for oncologists to take steps to detect it early and treat it effectively.

A new option where it is urgent to add options

For a difficult-to-treat cancer like salivary gland cancer, having a new treatment effective for many patients is an important advance, said Dr. Ezra Cohen, who specializes in treating the disease at the University’s Moores Cancer Center. of California in San Diego.

In the United States, only about 2,400 people a year are diagnosed with salivary gland cancer. There are many subtypes of salivary gland cancer, but in salivary ductal carcinoma, one of the most malignant, about 40% of patients have HER2-positive tumors, Dr. Cohen said.

“There is no standard first-line treatment” for advanced salivary gland cancer, he explained. He commented that with this new approval, T-DXd will now be considered an initial or first-line treatment for patients with HER2-positive disease, rather than a second-line treatment.

In another small study, strong responses were seen in salivary gland tumors using a different HER2-targeting drug called ado-trastuzumab emtansine (Kadcyla). Based on the results of that study and the T-DXd study, Dr. Cohen and other oncologists already use both drugs to treat some people with the disease, Dr. Cohen said.

“My experience [con estos] so far… it is extraordinarily good,” he said.

Dr. Meric-Bernstam said the strong and long-lasting tumor responses in people with gynecologic cancers are “very exciting.” She added that based on the results of the pantumor study, T-DXd has already been incorporated into widely used guidelines as a treatment option for HER2-positive gynecologic cancers.

Having this new FDA approval, both researchers explained, will help insurance cover the treatment.

“The mandate now,” Dr. Cohen emphasized, “is that all of our patients must be tested.” [para detectar la sobrexpresión de HER2] because we have effective therapies.”