Antibody-drug conjugates — a kind of molecular "smart bomb" — are emerging as an important form of targeted treatment across a variety of cancers.
In late 2022, a new treatment called mirvetuximab soravtansine was approved for patients with folate receptor alpha positive ovarian cancer that has become resistant to platinum-based chemotherapy. It was a significant milestone, marking the first new therapy for platinum-resistant ovarian cancer in nearly a decade.
It was also noteworthy because that therapy was an antibody-drug conjugate (ADC). ADCs consist of a drug, typically a very potent drug that would be dangerous to administer systemically, that is attached to an antibody that directs the drug specifically to cancer cells.
There are currently three ADCs approved for metastatic breast cancer and two approved for gynecologic cancers. Many more — potentially over 80 — new ADCs are under investigation across all forms of cancer. These drugs have been dubbed "a new frontier" in cancer therapy and are already seen as game changers in breast and gynecologic cancers.
Ursula Matulonis, MD
"Antibody drug conjugates are opening up a whole new avenue for therapy besides traditional chemotherapy," says Ursula Matulonis, MD, chief of gynecologic oncology in Dana-Farber's Susan F. Smith Center for Women's Cancers, who co-led the clinical trial of mirvetuximab soravtansine for ovarian cancer.
But the full potential of ADCs in breast and gynecologic cancers is yet to be realized. These drugs are intricate, their designs are flexible, and they are full of possibilities. Within the Susan F. Smith Center, several trials are underway to explore the ways that novel ADCs, ADCs in combination, and sequencing of ADCs can benefit patients.
The ABCs of ADCs
ADCs have been called smart bombs, biological missiles, even magic bullets. They do have some smarts and they also pack a potent punch.
The so-called smarts come from the presence of an antibody. Antibodies have a unique ability to home to a specific flag, or antigen, on a cell's surface. An antibody can differentiate a cancer cell from a healthy cell if the cancer cell overexpresses a flag that doesn't appear in abundance on healthy cells.
In the case of mirvetuximab soravtansine, the flag that identifies an ovarian cancer cell is called folate receptor alpha (FRalpha), which appears in close to 90% of recurrent high-grade serous ovarian cancer cases and is deemed "high" expression in approximately 35-40%. Other antigen targets that are currently used in ADCs include human epidermal growth factor receptor 2 (HER2) and a transmembrane protein called Trop2 in breast cancer. In cervical cancer, oncologists are using ADCs to target a receptor associated with blood clotting called tissue factor.
Targeting cancer using antibodies simplifies targeted therapy. In the past, researchers focused on finding mutated genes that fuel cancer growth. Once they found a molecular culprit, they needed to figure out how to turn the oncogenic mechanism off with a chemical drug.
"Now, we just need to find a little bit of target that's hanging out on the cell," says Sara Tolaney, MD, MPH, chief of breast oncology and associate director of the Susan F. Smith Center. "It's changing the way we develop drugs and the way we think about cancer."
Sara Tolaney, MD, MPH
If antibodies are the smarts of ADCs, the potency lies in the drug, which is connected to the antibody via a miniscule chemical linker. The variability of the linker chemistry, the drug, and the role of the antigen provide drug designers with extraordinary flexibility.
For instance, drugs used in ADCs range from agents that disrupt a cell's structure or damage DNA to agents that modulate the immune system. Drug developers can control how many of these toxic molecules each antibody carries. The linker can also be designed to release the drug under different conditions, such as inside a cancer cell or outside. And the antibody can play a role in the mechanism of action of the ADC or not.
"It's a complex structure," says Dana-Farber gynecologic oncologist Elizabeth K. Lee, MD. "There are many parts of an ADC that can be tinkered with that could potentially improve tolerability or efficacy. It's exciting because there's so much potential."
An Opportunity for Order
The ADCs approved for HER2-positive breast cancer are trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd). They both target HER2 using the antibody trastuzumab. The other, sacituzumab govitecan, targets Trop2 and is approved for hormone receptor positive and triple-negative metastatic breast cancer.
Nancy Lin, MD
"With these options, we have the potential to use ADCs across all three of the major breast cancer subtypes, which is very different than before," says Nancy Lin, MD, associate chief of breast oncology. "It really has opened up treatment options for a very large proportion of our patients with metastatic breast cancer."
Now that these treatments have become part of standard care, Dana-Farber and other researchers are looking for ways to expand their use. There are multiple clinical trials looking at moving the use of ADCs from second-line therapy to first line for patients with metastatic disease.
ADCs are also being investigated for use in early-stage disease. For example, T-DM1, which was originally approved for metastatic HER2-positive breast cancer in 2013, was approved in 2019 for use in early stage HER2-positive breast cancer as post-surgical treatment in certain higher-risk cases.
"ADCs have changed the landscape quite considerably," says Dr. Lin.
For HER2-positive breast cancer, the availability of two ADCs with the same smarts but different payloads spurred a trial called DESTINY-Breast03 to compare the two. T-DXd, which was approved in 2019, was found to be the preferred option but it does have more side effects.
There are also many novel ADCs under investigation. For instance, datopotamab deruxtecan (Dato-DXd) is in phase 3 clinical trials now for triple-negative and metastatic HR-positive breast cancer. It, like sacituzumab govitecan, targets Trop2 but carries the same drug as T-DXd.
The possibility that there might be more than one effective ADC for multiple forms of breast cancer raises important questions about how and when to use them. For patients with metastatic breast cancer, the current strategy is to treat patients indefinitely, moving from one treatment to the next, but how best to give multiple ADCs in sequence is still unclear.
"Some patients may be able to successfully go from one ADC to another," says Dr. Lin. "Is there an optimal order? We don't know the answer yet."
Ana Garrido-Castro, MD
To learn more, Dr. Tolaney and Dana-Farber breast oncologist Ana Garrido-Castro, MD, are running a multi-center clinical trial designed to answer the question specifically for T-DXd and Dato-DXd. It is one of the first trials in the nation to look at the question of ADC sequencing and resistance.
"The next big questions are how do we sequence these therapies and with what do we combine them?" says Dr. Garrido-Castro.
Smart Mixology
The question of how to combine ADCs with other drugs is also a focus in gynecologic cancers. The success of mirvetuximab soravtansine in ovarian cancer raised a new question: Could patients with endometrial cancer benefit from mirvetuximab soravtansine if their cancer expresses FRalpha.
The idea had merit, but another idea formed on its heels. Preclinical work in animal models had suggested that the ADC might alter the tumor microenvironment and make it more responsive to immunotherapies.
Now, in a phase 2 trial, Dana-Farber gynecologic oncologist Rebecca L. Porter, MD, PhD, is investigating the combination of mirvetuximab soravtansine with pembrolizumab, an immune checkpoint inhibitor, in patients with relapsed serous endometrial cancer that is FRaphla-positive.
"It made sense from a lot of different angles to bring these two therapies together in this specific subset of endometrial cancers," says Dr. Porter. "It's notoriously one of the most aggressive subtypes that is the very challenging to treat."
Another hypothesis about the potential of ADCs in gynecologic cancer emerged from an understanding of the inner workings of deruxtecan, the drug in T-DXd. This drug damages a cell's DNA in an attempt to kill it. What if that effect could be amplified?
A trial underway now is testing that idea by combining T-DXd with olaparib, a PARP inhibitor, which inhibits DNA repair mechanisms. Dr. Lee, who is leading the trial, speculates that the combination could both damage a cancer cell's DNA and prevent it from repairing itself, causing it to die. The antibody delivery mechanism could help limit this effect to cancer cells.
"It's meant to potentiate the DNA damage," says Dr. Lee.
The phase 1 trial is open for patients with any type of solid tumor, not just gynecologic, based on recent findings that have shown that T-DXd alone appears to work across tumor types for patients who are HER2-positive or HER2-low, meaning they express HER2, but at lower levels.
This inclusion of patients with low-level HER2 tumors might seem to contradict the central premise of ADCs, that their smarts derive from their ability to target flags that stand out, like an overexpression or abundance of HER2 on cancer cells compared to healthy cells.
But studies of T-DXd in breast cancer have shown that the drug has effects even in tumors assessed to be HER2-low. Similarly, in a study of the drug across all solid tumor types, patients with cases of low HER2 expression have shown responses. Exactly why T-DXd works with low levels of the target isn't clear yet.
"We are starting to wonder how much of the target we actually need," says Dr. Lee. "Each study is generating many new hypotheses for us to explore."