Finding Hope With Antibody-Drug Conjugates in Managing Breast Cancer

Before receiving a diagnosis of breast cancer nearly 20 years ago, life was going well for Hyunji Kim.

“The first diagnosis [was in] 2007, so almost 18 years ago, when I was 34 years old. I was just a housewife, and then raising kids, and [living a] happy life,” says Kim, now 52, of Los Angeles.

Kim, who had been diagnosed with hormone-receptor-positive breast cancer, underwent surgery, radiation and endocrine therapy. “Then, for nine years, nothing happened, and it was a very peaceful life,” she says.

She was diagnosed a second time, this time with triple-negative breast cancer, and she underwent surgery again as well as chemotherapy. The disease recurred, she underwent treatment, and a few months later she discovered that the triple-negative breast cancer had metastasized, or spread, to her liver.

Kim underwent treatment with the antibody-drug conjugate Trodelvy (saci­tuzumab govitecan-hziy) but was hospitalized due to side effects that included severe stomach pain, fever, vomiting and diarrhea, and her cancer grew while on the treatment. She was enrolled in a clinical trial evaluating ivermectin (an anti-parasite drug with immune stimulatory activity) and balstilimab (an immunotherapy) with limited success.

She is currently enrolled in a clinical trial evaluating another antibody-drug conjugate, the experimental treatment LCB84, and says that after two treatments, her liver metastasis is stable, and her other tumors have shrunk or receded.

A New Class of 'Designer Drugs'

Kim is a patient of Dr. Yuan Yuan — a professor of medicine, director of Breast Oncology and medical director of Breast Cancer Research at Cedars-Sinai Medical Center in Los Angeles, as well as a health sciences clinical professor at UCLA — who is on the cutting edge of antibody-drug conjugates.

“I usually describe antibody-drug conjugates as a new class of designer drug, where the target-specific antibody was attached to a small amount of chemotherapy [payload], in contrast to conventional chemotherapy with a larger amount of drug to enter the body,” says Yuan. “Here, the idea is to do a cancer cell-specific delivery.”

Antibody-drug conjugates, Yuan explains, usually have a “head” made up of an antibody targeted to a receptor such as the protein human epidermal growth factor receptor 2 (HER2) found on cancer cells, and that antibody is linked to a cytotoxic payload, such as a chemotherapy drug, that remains relatively stable outside of the targeted cell. Once it arrives at its delivery destination and enters the tumor cell, the linker breaks off and the drug is released.

“Then the drug can start its cytotoxic killing of the cancer cells. Then, after the drug has become effective and killed the cancer cell, it can potentially be released to the tumor microenvironment and potentially kill adjacent cells, even if those cells lack expression of that specific receptor, the so-called ‘bystander effect’” Yuan says.

LCB84, which targets the protein TROP2, is the subject of a phase 1/2 clinical trial evaluating it both alone and in combination with Keytruda (pembrolizumab) in the treatment of solid tumors including breast cancer. The chemotherapy attached to it acts differently than the one on Trodelvy, improving its chances of effectiveness.

“After two failed clinical trials, I experienced severe despair, but I have gained hope through this new drug,” Kim says. “The previous trials had significant side effects, including leukopenia [a low count of leukocytes, a type of white blood cell], but this new medication has been much easier to tolerate, with only slight appetite loss and fatigue. If there are other patients in a similar situation, I would strongly recommend it.”

There are now more than 150 antibody-drug conjugates being studied in clinical trials across cancer types, says Dr. Nancy Lin, the associate chief of the Division of Breast Oncology for the Dana-Farber Cancer Institute Susan F. Smith Center for Women’s Cancers in Boston and the director of Dana- Farber’s Metastatic Breast Cancer Program, and a member of CURE’s advisory board.

“It’s a really, really hot area of clin­ical trials and drug development, and I think that’s because there have been a number of success stories,” Lin says. “So it’s, in a way, a very modular idea, because if you change the target — meaning you change what the drug goes after, the marker on a cell surface — and you can change what chemotherapy is attached to that homing device, then you have many, many different combinations that could be tried.”

Kadcyla (ado-trastuzumab emtansine, T-DM1) made history as the first antibody-drug conjugate approved for the treatment of a solid tumor when, in 2013, it received approval from the Food and Drug Administration (FDA) for the treatment of patients with metastatic, HER2-positive breast cancer who had previously been treated with Herceptin (trastu­zumab) or taxanes.

There are now three antibody-drug conjugates approved by the FDA for the treatment of breast cancer: Kadcyla, followed by Enhertu (trastuzumab deruxtecan, or T-DXd), which also targets HER2, and Trodelvy, which targets TROP-2.

The relative stability of the markers antibody-drug conjugates search out in breast cancer makes that cancer type a potent target for these treatments, Lin explains.

“If you think about how could cancers become resistant to medicines, well, if they hide the target, then the drug can’t find it anymore,” Lin says. “But for example, in patients who have HER2-positive breast cancer, that HER2 target is quite stable across the patient’s disease course and so, for the most part, it stays there. That means there’s a potential to develop sequenced drugs where you just switch out — you could continue to target HER2, but you just switch out the chemotherapy that’s attached to the antibody-drug conjugate.”

The experts who spoke with CUREsay researchers are looking into the prospect of sequencing one anti­body-drug conjugate after another.

“We have no idea of [the best approach to] sequencing,” says Yuan. “What is the best sequence, or what is best for the patient sitting in front of us in the clinical role, and what makes the most sense? Do we have scientific data to guide those treatments? Currently, right not, there is missing data. There’s a huge need to understand sequencing questions and also [questions] as you move into the combination strategy.”

There’s a lot to be excited about in the world of antibody-drug conjugates right now, as Dr. Erika Hamilton notes.

“Overall, we have seen antibody-drug conjugates beat single-agent chemotherapy in every trial in metastatic breast cancer, so really, the activity, that’s clearly something that excites us,” says Hamilton, a medical oncologist and the director of Breast Cancer Research at Sarah Cannon Research Institute in Nashville.

“Antibody-drug conjugates are also making us question what we previously thought true in breast cancer,” Hamilton says. “For example, [we thought] you needed to have high HER2 expression on your cancer to benefit from a HER2 agent, [which was] certainly the case for [Kadcyla]. … This doesn’t appear to be the case for newer drugs [such as Enhertu] … [where] we have an approval for high [expression], we have an approval for low [expression], and now we have a randomized trial showing benefit even in what we’ve coined ultra-low [expression], which is an [immunohistochemistry] of zero with very little expression. Then there are other antibody-drug conjugates, such as [Trodelvy], and this is a TROP2-targeting antibody-drug conjugate. We don’t even need to test for the marker. It’s really across the board whether a tumor has high or low TROP2; it beats standard chemotherapy. So [it’s been] really kind of a big paradigm shift in breast cancer, to be quite honest.”

However, Hamilton says while it is tempting to think about antibody-drug conjugates as a class of drugs, they each have distinct features worth considering, particularly regarding side effects.

“[Kadcyla] does not have hair loss, has low platelets as a side effect and we really don’t see much ILD [interstitial lung disease, or scarring of the lung tissue]. In our newer antibody-drug conjugates, [Enhertu, for example,] the most prominent side effect is nausea, and we also see alopecia [hair loss] and ILD rates of 10% to 15% among treated patients. [Trodelvy], on the other hand, [its] most prominent side effects are neutropenia [a low count of neutro­phils, a type of white blood cell], and diarrhea,” she says. “So, as somebody who is prescribing this, or as patients who are taking this, we don’t want to think about these drugs as inter­changeable or if you have seen one, you have seen them all. They are very different drugs. They have very different side effects. We really want to think about them individually.”

Among Hamilton’s patients is Karen Broyles, 66, of northeastern Tennessee. Before receiving her diagnosis of HER2-positive breast cancer in 2007, she considered herself to be a healthy, athletic and active individual.

“I always thought I was just healthy as a horse,” says Broyles. “I was really shocked — well, not really shocked, because I had a lump that I was concerned about that took a while for the doctors to actually recognize and realize there was something wrong.”

By the time she received her diag­nosis, the cancer had spread to her lungs and back, she says. Since then, she says, she’s been on “one form or another” of treatment, including several clinical trials.

Broyles has been on Enhertu for about two years and has undergone more than 40 treatments with the drug, she says.

“I’m doing good,” she says. “They did have to, [for] the past two treatments, reduce my dosage by 15%, but that’s because of my platelets being so low. After they did that, honestly, the side effects are pretty much nil, except for the hair thinning.”

Broyles, who works as a data integrity analyst, continues to live an active lifestyle. “It’s really not affected my energy level,” she says. “Of course, I’m just an active person. I still work a full-time job, and I still do extracurricular activities.”

The field of antibody-drug conjugates, Yuan says, “really brought some hope for oncologists, for patients when we are encountering extremely chemotherapy-resistant disease.”

Meanwhile, the research continues, Hamilton says, with limitless possibilities. “Our options are really endless in terms of different payloads, different antibody targets,” she says. “I think we’re going to be seeing a lot more antibody-drug conjugates in this space.”

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