The Expanding Role of ADCs

LORI COSSOU REMEMBERS connecting with Emma Waterman Mon through a Facebook group for people with metastatic cancer who were interested in traveling. In the spring of 2026, both women started treatment with an antibody-drug conjugate (ADC) called Datroway (datopotamab deruxtecan). Looking to educate themselves, they also joined a public Facebook group for people interested in learning about the drug and sharing their experiences.

Although they had different types of breast cancer, Cossou and Waterman Mon had some similar treatment experiences. Both were initially diagnosed with early-stage cancer, and their treatment included double mastectomy and chemotherapy. Cossou, of Goodman, Missouri, was diagnosed with stage IB triple-negative breast cancer, which meant her cancer tested negative for traditional biomarkers that often respond to targeted treatments, such as hormone therapy or HER2-targeted therapy. Waterman Mon, who lives in West Chester, Pennsylvania, was first diagnosed with early-stage hormone receptor-positive disease, which meant hormone therapy that deprived her body of or blocked estrogen could be used to keep her cancer from coming back.

Cossou learned the cancer had spread to her lymph nodes and lungs in January 2023, a year and a half after she completed treatment for early-stage disease. Waterman Mon received her initial diagnosis at age 36 in 2008, when her two children were under the age of five. In 2018, she had a suspicious lump on her right side biopsied, which indicated her cancer was back. Initial scans showed cancer in her lungs.

In the spring of 2026, Cossou and Waterman Mon both started receiving infusions of Datroway every 21 days. The treatment marked Cossou’s seventh line of treatment since her initial diagnosis and Waterman Mon’s eighth.

The ADC Era

A growing class of targeted cancer therapies, ADCs include three main components: an antibody that recognizes a specific protein, or antigen, on cancer cells; a cancer-killing drug that’s most often a form of chemotherapy; and a linker that connects the two.

Sometimes referred to as “smart bombs” or “targeted missiles,” ADCs can recognize proteins found on cancer cells and bind to those targets, says Aditya Bardia, a medical oncologist at UCLA Health Jonsson Comprehensive Cancer Center in Los Angeles. Once this occurs, the ADC is taken into the cell, where it delivers a toxic payload. “It’s definitely a very hot field right now,” Bardia says. “ADCs are essentially replacing chemotherapy. The idea is to give higher doses of chemo, if you will, to cancer cells but not the normal cells.”

Although more ADCs have been coming to market recently, the technology behind them is not new. In 2000, the Food and Drug Administration (FDA) first granted accelerated approval to the ADC Mylotarg (gemtuzumab ozogamicin) for certain older adults who experienced relapse of CD33-positive acute myeloid leukemia and who were not considered candidates for cytotoxic chemotherapy. The drug manufacturer had voluntarily withdrawn the drug from the U.S. market in 2010 after a confirmatory trial failed to verify its clinical benefit and raised safety concerns. However, Mylotarg returned to the market in 2017 with a lower dosing regimen and broader indications. Its initial accelerated approval—an FDA pathway provided to new drugs based on surrogate endpoints, such as tumor response, that suggest clinical benefit—provided an important proof of principle: that an antibody could deliver a highly potent drug to cancer cells.

Other ADC approvals in blood cancers followed, including the 2011 approval of Adcetris (brentuximab vedotin), which targets CD30 on cancer cells, for certain previously treated lymphomas. In 2013, the FDA approved Kadcyla (ado-trastuzumab emtansine) for previously treated metastatic HER2-positive breast cancer, marking the first FDA approval of an ADC for a solid tumor. Kadcyla combined trastuzumab, an already established HER2-targeted antibody, with a potent cancer-killing drug called DM1, allowing the antibody to deliver the drug to HER2-positive cells. In December 2019, the FDA approved Enhertu (trastuzumab deruxtecan) for previously treated metastatic HER2-positive breast cancer—an indication that later expanded to breast cancer with low and, more recently, very low levels of HER2 expression.

Datroway, the ADC that Cossou and Waterman Mon started taking, targets Trop-2, a protein found at abnormally high levels in many cancers, including breast cancer. The ADC was initially approved Jan. 17, 2025, for adults with unresectable or metastatic hormone receptor-positive, HER2-negative breast cancer who had previously received endocrine therapy and chemotherapy for advanced disease.

More recently, on May 22, 2026, the FDA expanded Datroway’s approval to adults with unresectable or metastatic triple-negative breast cancer when they cannot receive PD-1/PD-L1-directed immunotherapy. This approval was based on results of the TROPION-Breast02 trial, which included 644 patients. The study found the ADC extended median progression-free survival to 10.8 months, compared with 5.6 months with chemotherapy. Median overall survival was 23.7 months with Datroway and 18.7 months with chemotherapy.

The indications for Datroway have expanded to other cancer types as well. On June 23, 2025, the FDA granted Datroway accelerated approval for people with locally advanced or metastatic EGFR-mutated non-small cell lung cancer (NSCLC) who had previously received EGFR-directed therapy and platinum-based chemotherapy. The research leading to the approval was based on a pooled analysis from two studies. One of the studies was the phase III TROPION-Lung01 trial, which compared the safety and efficacy of Datroway to that of the chemotherapy drug docetaxel in 604 people with previously treated advanced or metastatic NSCLC. In the study, median progression-free survival was 4.4 months with Datroway, compared with 3.7 months with docetaxel. Among people who had nonsquamous NSCLC that carried actionable genomic alterations, most commonly EGFR mutations, progression-free survival was 5.7 months with Datroway, compared with 2.6 months with docetaxel.

The phase II TROPION-Lung05 trial tested the ADC specifically in people whose NSCLCs carried specific actionable genomic mutations, including 78 people with EGFR mutations. In that study, about 44% of people with EGFR mutations responded to Datroway.

The FDA ultimately pooled results from 114 people with EGFR-mutated lung cancer enrolled in TROPION-Lung01 and TROPION-Lung05. This analysis found 45% responded to Datroway, with responses lasting a median of 6.5 months. Those results led to the FDA’s accelerated approval of Datroway for previously treated locally advanced or metastatic EGFR-mutated NSCLC.

“The exciting thing is that we have a number of different antibody-drug conjugates that are showing incredible promise across multiple tumor types,” says Jacob Sands, a thoracic medical oncologist at Dana-Farber Cancer Institute in Boston and an investigator on the TROPION trials. He notes, for example, the more pronounced benefit of Datroway in lung cancers carrying EGFR mutations. “Over the last few years, we’ve seen some big advances with new FDA approvals, as well as other drugs that have really shown, in some cases, very impressive results [in clinical trials].”

Moving to the Front Line

Another ADC, Padcev (enfortumab vedotin), was first granted FDA accelerated approval in December 2019 for adults with locally advanced or metastatic urothelial cancer who were previously treated with immunotherapy and platinum-based chemotherapy. The approval has improved outcomes for people with advanced cancers of the bladder and genitourinary tract, says Vadim Koshkin, a genitourinary medical oncologist at UCSF Helen Diller Family Comprehensive Cancer Center in San Francisco. Oncologists started prescribing Padcev to patients in early 2020 just before the start of the COVID‑19 pandemic, Koshkin says. He notes that there are people who were diagnosed at that time with advanced urothelial cancer “who are still alive today, who I think would have really succumbed to their disease had this drug been introduced even a year later.”

The antibody in Padcev targets Nectin-4, a protein present at high levels on the surface of most urothelial cancers but absent in most healthy adult cells and tissues. Once inside cells, the ADC delivers an agent that disrupts the formation of microtubules, cytoskeletal elements that cells require to divide and grow. As a result, it forces those cells into a process called apoptosis that leads to their death.

Padcev received regular approval in 2021, after clinical trials confirmed increases in overall survival compared with chemotherapy. On Dec. 15, 2023, the FDA expanded approval of Padcev in combination with the immunotherapy drug Keytruda (pembrolizumab) as a first-line option for advanced urothelial cancers. On Nov. 21, 2025, the FDA expanded approval for this ADC-immunotherapy combination again, this time for use before and after surgery for adults with muscle-invasive bladder cancer who are not eligible for the chemotherapy drug cisplatin. On July 10, 2026, the FDA expanded that perioperative indication with Keytruda to include all adults with muscle-invasive bladder cancer who are candidates for surgery to remove their bladder, including those eligible for cisplatin.

The combination of Padcev and Keytruda as an established first-line regimen could extend five-year overall survival rates for people with advanced-stage disease from between 5% and 10% to closer to 40%, Koshkin says. Although five-year overall survival data are not yet available for those taking the combination, updated results presented at the 2026 American Society of Clinical Oncology Annual Meeting support that possibility. In that analysis, 44% of people with previously untreated locally advanced or metastatic urothelial cancer who received Padcev and Keytruda were alive at 3.5 years, compared with about 25% of those who received platinum-based chemotherapy. Median overall survival was 33.6 months with the combination, compared with 15.9 months with chemotherapy.

Before Padcev and Keytruda became a first-line option, platinum-based chemotherapy had long been the standard for muscle-invasive bladder cancer, but it typically came with toxicity and limited effectiveness. In addition, up to half of people with metastatic urothelial cancer are not eligible for systemic chemotherapy due to other health conditions. Koshkin says he anticipates improved outcomes for more people with the disease now that the ADC is approved for people with high-risk, early-stage bladder cancers.

“I think we will be actually curing a lot more patients by using this combination earlier, prior to and following surgery for bladder cancer,” Koshkin says. “There have been really significant advances just over the past five to six years in urothelial cancer that have completely transformed this space.”

Considering Quality of Life

In general, ADCs allow for the use of chemotherapeutics that might otherwise be too toxic to be delivered straight to the cancer cell, Koshkin says. Still, the design that delivers a potent cancer-killing drug more selectively to cancer cells can damage healthy cells and cause serious side effects. Urs Weber, a thoracic medical oncologist at the University of Colorado Cancer Center in Aurora, says side effects can arise if the ADC linker releases the chemotherapy component too early before entering cancer cells.

Common side effects that occur with ADCs include fatigue, nausea, low blood cell counts and diarrhea, while some ADCs come with other toxicities. For example, Enhertu can cause interstitial lung disease or pneumonitis, which can occasionally be fatal. Padcev can cause peripheral neuropathy and serious skin reactions. Trodelvy (sacituzumab govitecan) commonly causes low white blood cell counts and diarrhea, and Elahere (mirvetuximab soravtansine), an ADC for some previously treated ovarian cancers, can cause eye problems, such as blurred vision and damage to the cornea.

Almost immediately after starting treatment, Cossou and Waterman Mon began experiencing side effects. Cossou says she had excruciating mouth sores, and Waterman Mon’s oncologist lowered her dose after she reported fatigue, trouble thinking and dizziness. Despite the treatment, Cossou’s cancer has showed signs of progression, so she has stopped taking Datroway and is starting on a different treatment. While she was hoping Datroway would provide more disease control, she also notes that a previous ADC, Trodelvy, had controlled her disease for almost a year.

Besides these side effects, there is another downside. Although ADCs can be very effective, only a minority of patients who take them go on to live without disease progression for years, Koshkin says. Instead, cancers typically develop resistance to ADCs and eventually stop working. Researchers are working to understand how cancers become resistant to ADCs and whether ADCs with new targets, payloads or linkers could be effective once first-line ADCs stop working, Koshkin says. “We’re only beginning to scratch the surface of understanding how these drugs work, how the different resistance mechanisms develop and the toxicities that can be caused as a result of these drugs,” he says.

One strategy to overcome resistance relies on treatment combinations, including using immunotherapies. In a phase III clinical trial published June 27, 2026, in the Lancet, 413 previously untreated people with advanced PD-L1-positive NSCLC received either sacituzumab tirumotecan (sac-TMT) plus Keytruda or Keytruda alone. The combination reduced the risk of disease progression or death by 65%. In addition, 70.2% of people receiving the combination had an objective response, compared with 42% of those receiving Keytruda alone—although the data were not yet mature enough to determine any benefit to overall survival.

Researchers can further refine an ADC’s target, payload and linker to develop alternatives for use after resistance arises, Bardia says. He says new ADCs in development include designs with bispecific antibodies or dual payloads, allowing them to recognize more than one target or deliver two cancer-killing medicines at once. Researchers are also exploring payloads other than traditional chemotherapy agents.

Sands says he believes the current chapter in ADC development marks the beginning of a larger story. “I see these as really the first generation of ADCs, and [the data are] showing us that this specific technology is effective and viable. And now the question becomes ‘What can we use as the payload aside from cytotoxics? Is there something that we can deliver to cells that ends up having less toxicity and is even more effective?’” Sands says. “This [early success] is just a foundation upon which to build out other, even more effective therapies.”