Antibody drug conjugates: A shift in treatment options for solid tumors

Antibody drug conjugates have existed for years, but several recent advances are helping to refine how these cancer drugs work, expanding our understanding to help overcome their challenges and, ultimately, extending their benefit to more patients.

“Antibody drug conjugates are an exciting field of drug development,” says Funda Meric-Bernstam, M.D., chair of Investigational Cancer Therapeutics.

Antibody drug conjugates target cancer cells with a powerful punch

Potent cancer drugs are typically unable to differentiate cancer cells from normal ones. Antibody drug conjugates overcome this challenge by linking the drug to a monoclonal antibody specifically chosen to target and deliver the drug to cancer cells.

“We conjugate a cancer drug, such as a chemotherapy that’s highly toxic, to an antibody that targets a protein on the surface of a cancer cell,” says Meric-Bernstam. “The thought is that by delivering much higher concentrations of chemotherapy to cancer cells, we have a greater therapeutic index.” Because the drug payload is directly carried to the cancer cell, it reduces the side effects a patient may experience.

Antibody drug conjugates are administered intravenously, and the frequency of treatment depends on the specific drug. Many antibody drug conjugates are being used or explored to treat metastatic disease, and patients continue to receive infusions as long as they’re benefitting from treatment.  However, antibody drug conjugates are also being explored to treat patients with earlier stage disease.

HER2 serves as a target for antibody drug conjugates across several cancer types

The first antibody drug conjugate used to treat solid tumors was T-DM1, a combination of the HER2 protein-targeting monoclonal antibody trastuzumab and a chemotherapy drug called DM1.

T-DM1 is approved to treat metastatic breast cancer with overexpression of HER2, meaning there are high levels of HER2 protein on the surface of the cancer cell. It’s also approved to treat breast cancer with HER2 amplification, which means there is a higher-than-normal number of copies of the HER2 gene.

The level of HER2 expression of a tumor cell is determined by an immunohistochemistry (IHC) test. HER2 positive cancers are defined as either IHC 2+ with amplification or IHC 3+, with the higher number of IHC denoting a higher level of HER2 protein.

In addition to breast cancer, HER2 can also be found in several other types of cancers including stomach, lung, gynecologic and bladder cancers, but the levels of HER2 expression vary across tumor types.

DESTINY-PanTumor02 and other clinical trials aim to expand antibody drug conjugate benefit

The next evolution of HER2-targeting antibody drug conjugates came quickly with the introduction of the trastuzumab deruxtecan. Like T-DM1, it shows strong efficacy in tumors with high levels of HER2. But unlike T-DM1, it has also been shown to be effective against breast cancers with lower HER2 levels.

“Trastuzumab deruxtecan represents a rapid evolution in antibody drug conjugate technology that may be more efficacious. It has opened the door for many more patients to potentially benefit from these treatments,” says Meric-Bernstam.

Trastuzumab deruxtecan is currently approved by the Food and Drug Administration (FDA) to treat patients with HER2 positive breast cancer, HER2 low breast cancer (HER2 2+ or 1+ tumors without amplification), HER2 positive gastric cancer and HER2 mutant lung cancer.

Yet patients with more difficult-to-treat HER2-expressing cancers are without a targeted treatment option.

Meric-Bernstam is leading several clinical trials investigating antibody drug conjugates. One study is the DESTINY-PanTumor02 clinical trial, a multicenter basket clinical trial investigating trastuzumab deruxtecan in patients with solid tumors with IHC 2+ or 3+ levels of HER2 expressions.

New targets may lead to new antibody drug conjugate options for patients

The burst of development in antibody drug conjugates can be credited to the progression of the technology used to link the drugs’ components as well as it can be attributed to improvements to the efficacy of the payload drugs.

As antibody drug conjugates have evolved, more targets have been identified. “We now see multiple targets moving forward as well as different strategies to treat the same patient population,” says Meric-Bernstam.

For example, the TROP2 protein is overexpressed in several epithelial tumor types, including triple-negative breast cancer, hormone receptor positive breast cancer and bladder cancer. Sacituzumab govitecan is approved to treat patients with these TROP2 positive cancers, and other drugs, such as datopotamab deruxtecan, are being investigated to treat the same TROP2 positive cancers.

In addition, enfortumab vedotin has been explored to target tumors overexpressing the nectin protein. Although nectin is overexpressed in other tumor types, thus far the drug has been approved to treat patients with nectin positive bladder cancer.

Improved understanding will lead to better patient selection
Over the next few years, Meric-Bernstam expects several more antibody drug conjugates to emerge. “I think we’ll see multiple antibody drug conjugate options for patients,” she says.

New questions will arise as more antibody drug conjugates that target the same proteins in the same patient population are developed. To improve patient selection, Meric-Bernstam says more research is needed to:

• understand the influence of a protein’s expression level on the efficacy of the drug
• evaluate if and how previous treatment with a different antibody drug conjugates and other chemotherapies will impact efficacy and sequencing
• better predict patient response to the various payload options
• anticipate the potential side effects

Although side effects vary between the antibody drug conjugates, Meric-Bernstam warns there is still the risk of side effects related to bone marrow, lung inflammation and neuropathy. Lastly, she predicts that there will be more research exploring rationale combinations, too.

With so many advances made in the field in such a short time, Meric-Bernstam sees antibody drug conjugates as shifting the options for patients with difficult-to-treat solid tumors.

“We’ve seen so many antibody drug conjugates demonstrate benefit to patients with difficult-to-treat tumors that, in my mind, they’re the next pillar of cancer therapeutics,” says Meric-Bernstam.

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