ADCs Make Their Mark

IN 2009, SHEILA MARIE JOHNSON SNEEZED at her desk and noticed a burning sensation in her chest. “I thought, ‘That was weird,’” she recalls. A week or two later, with another sneeze, it happened again. Johnson, then 43, went to her doctor, who did a breast exam and ordered a mammogram.

Mammograms were not new to Johnson, who lives in Swansea, Illinois, and was a senior master sergeant in the U.S. Air Force at the time. She had been getting screened annually ever since her mother had died from metastatic breast cancer five years earlier. This time, however, the radiologist saw something concerning in the images of Johnson’s dense breast tissue. “Do you see all this white stuff in your right breast?” Johnson remembers the radiologist asking her, pointing to the images on a computer screen. “That’s breast cancer.”

Additional scans and biopsies revealed that the cancer had already spread to Johnson’s lymph nodes, liver and ribs. The five-year relative survival for breast cancer that has spread to distant parts of the body according to even the most current statistics is just 31%, but her doctors stressed that the disease could be treated even though Johnson had aggressive stage IV breast cancer.

Johnson had her right breast removed and a breast reduction on her left side. The cancer cells tested positive for estrogen and progesterone receptors, so she had surgery to remove her ovaries to limit hormones that could fuel the cancer’s growth. Because her cancer had an abundance of HER2 proteins, she was a candidate for targeted therapy that blocks HER2 proteins on cancer cells from receiving growth signals. One such therapy, Herceptin (trastuzumab), kept the cancer controlled for more than eight years. Later, when the cancer progressed, her doctors added another HER2-targeted therapy called Perjeta (pertuzumab) to Herceptin, and she started taking the chemotherapy drug docetaxel.

In July 2018, a cancer progression in Johnson’s fourth rib would launch a new treatment chapter. Her oncologist suggested she consider joining a clinical trial that was testing an experimental drug then known as DS-8201 or trastuzumab deruxtecan. Her enrollment in the study would make her one of the first people in the world to receive the drug that now goes by the brand name Enhertu—a type of antibody-drug conjugate (ADC) that has been described as a biological missile delivering toxic drugs straight to cancer cells.

The ABCs of ADCs

Today Enhertu is one of more than a dozen ADCs that are approved by the Food and Drug Administration (FDA) to treat various blood and solid cancers. ADCs add a new option to the list of cancer drug treatments that includes chemotherapy, immunotherapy and targeted therapy.

ADCs include three key parts: An antibody targets proteins found on the surface of cancer cells, and a linker joins the antibody to the third component, a chemotherapeutic drug or other molecule that is toxic to cancer. Once inside a cancer cell, the linker breaks down to release the drug’s cytotoxic payload, destroying the cancer cell.

“The whole premise of ADCs started with the idea that we could deliver in a targeted manner high doses of effective chemotherapies to cancer cells and spare healthy tissue from those agents,” says Sara Tolaney, a breast oncologist at Dana-Farber Cancer Institute in Boston.

While the success of ADCs has been recent, the concept behind them is not. In the early 20th century, the German physician-scientist Paul Ehrlich observed that chemical dyes interact differently with various cell structures. This observation led him to postulate that cells have certain “side chains” or receptors that bind specific proteins. He proposed that future drugs could act as “magic bullets” homed in on their intended cellular target.

The first clinical trials to prove the feasibility of the approach occurred in the 1980s in metastatic colorectal and ovarian cancer, but many early trials had a high failure rate. At the time, ADCs were engineered using mouse antibodies, which were often attacked by the human immune system. However, improvements in the technology to target cancers, including advances that made animal antibodies more similar to human antibodies, led to ADCs’ first clinical success: In 2000, the FDA granted accelerated approval to Mylotarg (gemtuzumab ozogamicin) for older adults with relapsed acute myeloid leukemia (AML) whose cancer had tested positive for CD33, a protein found in abundance on the surface of some leukemia cells. The approval marked what an article in Nature called “the beginning of [the] ADC era of cancer targeted therapy.”

Mylotarg includes an anti-CD33 antibody combined with an anti-tumor antibiotic and a drug linker. However, the results of follow-up clinical trials in people with AML showed no clinical benefit and more deaths in the group receiving Mylotarg versus chemotherapy, which led the drug manufacturer to voluntarily withdraw the drug in 2010. The FDA approved it again for relapsed or refractory CD33-positive AML in children and adults in 2017 based on new data showing that a lower dose and a new dosing schedule made Mylotarg more tolerable, and that it was indeed more effective than the standard of care.

ADCs have since gained approval for treating several blood cancers, including relapsed or treatment-refractory leukemias and lymphomas as well as multiple myeloma. The first ADC for solid tumors came in 2013 with FDA approval of Kadcyla (ado-trastuzumab emtansine or T-DM1) for advanced-stage HER2-positive breast cancer that had been treated previously with trastuzumab and a taxane chemotherapy. On top of the approved ADCs, more than 100 ADC candidates are now in different stages of development and clinical testing. The technology also has gotten better, Tolaney says, as researchers have learned how to make linkers that are freed more easily once inside cancer cells and have developed antibodies that better target more cancers.

“Not only are they [ADCs] more effective, but they have also changed the way we think about drug development,” Tolaney says.

Before ADCs, targeted therapies aimed for the protein or proteins that were driving a particular cancer’s growth. The goal was to turn off or block the growth signal and stop a cancer in its tracks. But there are often multiple drivers of cancer growth, which can change over time and cause treatment resistance. The early successes of ADCs led to an important “paradigm shift,” Tolaney says, which has provided an alternative way to selectively target and destroy cancer cells.

“We no longer need to find oncogenic drivers,” she says. Instead, scientists can use nearly any protein on a cancer’s surface—so long as it isn’t commonly expressed on normal cells—to deliver chemotherapy through a highly potent antibody-drug conjugate. “It’s a dramatic change,” Tolaney says.

Aiming for Other Targets

Johnson was one of 184 patients who participated in a trial that led to Enhertu’s approval for patients with HER2-positive breast cancer that has metastasized or can’t be surgically removed. Almost 61% of patients who took the drug in the trial responded with a median time of response of 14.8 months. Tolaney notes that these early successes in breast cancer not only offered a highly effective treatment for women with metastatic breast cancer, but also the first evidence that ADC technology could work in solid cancers too.

In addition, Enhertu could also be effective for other cancers that express an abundance of HER2 proteins, including in the bladder, pancreas, ovaries, lungs and stomach. In 2021, the FDA expanded Enhertu’s approval to include adults with advanced HER2-positive gastric or gastroesophageal junction adenocarcinoma, if they had already received another trastuzumab-based regimen. In one study, 40.5% of patients who received Enhertu for this cancer, which starts in the stomach or where the esophagus meets the stomach, responded to treatment, compared with 11.3% of those who got standard chemotherapy. Patients who took Enhertu lived an average of 12.5 months versus 8.4 months for those treated with chemotherapy. Then, in August 2022, HER2-positive metastatic non-small lung cancer (NSCLC) was added to the list of approved indications for Enhertu.

New research shows that patients whose cancer expresses low levels of the HER2 protein can also benefit from Enhertu. A study published July 7, 2022, in the New England Journal of Medicine included adults with metastatic breast cancer that expresses low levels of the HER2 proteins and showed that Enhertu reduced these patients’ risk of disease progression or death by 50% over standard chemotherapy. The median overall survival with Enhertu was 23.4 months compared with 16.8 months with chemotherapy for this group.

The finding is especially significant because up to 20% of breast cancers have high levels of HER2 proteins, but about 60% of breast cancers traditionally categorized as HER2-negative express HER2 at low levels. The research, which led to the drug’s FDA approval for patients with HER2-low breast cancer, has vastly expanded the number of women who might benefit from treatment with Enhertu.

“We now know this works even in HER2-low breast cancers that aren’t driven by HER2,” Tolaney says. It’s a development she calls “revolutionizing.” When the data showing Enhertu was effective in HER2-low breast cancers were presented at the American Society of Clinical Oncology Annual Meeting in June 2022, the audience greeted the news with a lengthy standing ovation.

“This is a really transformational time for ADCs,” says Funda Meric-Bernstam, who is the chair of the department that oversees early-stage clinical trials at the University of Texas MD Anderson Cancer Center in Houston. “ADCs have had a dramatic impact on cancer outcomes already, and I expect a lot more to come over the next several years. We need to think of them as an additional pillar of cancer management.”

The HER2 protein is just one of many potential solid cancer targets for ADCs. For instance, Trodelvy (sacituzumab govitecan) targets a protein called TROP2 and is approved to treat metastatic or unresectable triple-negative breast cancer and urothelial cancer. In November 2022, the FDA approved another ADC, called Elahere (mirvetuximab soravtansine), which uses a folate receptor to gain access to cancer cells and is approved to treat ovarian cancer and other cancers that form in the lining of the fallopian tube or peritoneum. Many different tumor types express the same targets, which could extend ADCs’ benefits to other cancers. As a result, Meric-Bernstam says, she is “excited to see how these targets and others will play out.”

ADCs are also now the standard treatment for advanced-stage bladder cancer, says Lawrence Fong, a genitourinary oncologist and cancer biologist at the University of California, San Francisco, with options including nectin-4–targeted Padcev (enfortumab vedotin) and TROP2-targeted Trodelvy. Fong foresees ADCs becoming an option in the future for other cancers, including metastatic prostate cancer and early-stage cancers.

“[These ADCs] have significant activity in metastatic urothelial cancer,” Fong says. “They’re FDA-approved and are slowly migrating to earlier and earlier states of disease. ADCs together with [the immunotherapy drug Keytruda (pembrolizumab)] have what appears to be even greater activity. As they move forward to earlier lines of treatment, one of the hopes for those of us in the field is that ADCs may supplant chemotherapies.”

Unanswered Questions

ADCs come with drawbacks, limitations and uncertainties. For instance, it’s not yet clear if using ADCs in earlier-stage cancers will be both tolerable and better than the current standard of care. In addition, if the cancer stops responding to the ADC, physicians may not be certain what is fueling that resistance: changes to the cancer cell surface that prevent the ADC from gaining entry to the cell or changes in the way the cell responds to the toxic payload. With a better understanding of why resistance occurs, physicians might better select the next therapy.

While the targeted nature of ADCs to deliver chemotherapy straight to cancer cells should, in theory, cause fewer side effects than standard chemotherapy, the use of ADCs still comes with potentially serious risks and side effects that require careful monitoring, including interstitial lung disease, neuropathy and eye toxicity, Tolaney and Meric-Bernstam both note. Enhertu comes with warnings about heart problems, low white blood cell counts (neutropenia), and potentially severe or even life-threatening lung problems.

Johnson found Enhertu’s side effects, including nausea and acid reflux, “brutal,” but she kept on using it. After three years of taking Enhertu as part of the ongoing clinical trial, she developed COVID-19, which she says “messed up” her lungs. When she developed pneumonia, her doctor suggested a break from Enhertu, because of the drug’s potential to worsen lung problems. Ten months later—more than 13 years after her initial diagnosis—she started back on Enhertu in October 2022. But in February 2023, she learned the drug that had kept her cancer stable for more than three years was no longer working. In April 2023, she started treatment with the chemotherapies cyclophosphamide, methotrexate and fluorouracil along with HER2-targeted medications Perjeta and Herceptin. When her cancer showed signs of progression, her doctors switched the chemotherapy regimen to paclitaxel.

“ADCs work. Some people get four years, some get six months’ time,” Johnson says. “Every cancer is different.” Her advice to anyone newly diagnosed: It is OK to be scared. “If you have any questions or don’t understand, continually ask and advocate for yourself.” While Enhertu alone is no longer an option for her, she says she does not think the drug failed her. Her decision to take a leap of faith and enroll in the clinical trial in 2018 “gave me four years of life,” she says. For that, she adds, “I’m eternally grateful.”