A 2026 'State of the Union' on ADCs
Recent ADC approvals are reshaping first-line and biomarker-driven treatment paradigms across multiple solid tumors. The move of trastuzumab deruxtecan and pertuzumab into first-line HER2+ metastatic breast cancer and expansion into HER2-low populations signals a broader shift toward earlier, target-defined use.
Patient selection is becoming more nuanced, with efficacy tied to precise biomarker expression. In practice, this raises the bar for comprehensive molecular profiling and may expand testing beyond traditional thresholds to capture patients eligible for ADCs.
Industry Buzz
One of the main areas of research is the development of conditionally released ADC linkers or second-generation linkers that offload the payload in the tumor microenvironment in order to increase the efficacy while reducing the systemic toxicity or off-target killing of normal cells.
—Shou-Ching Tang, MD, PhD, FACP, FRCPC
Antibody-drug conjugates (ADCs) are a rapidly expanding class of targeted cancer therapies that house three potent elements: a monoclonal antibody (designed to look like the body’s own antibodies), a powerful cytotoxic drug (known as the payload), and a chemical linker that bridges the gap between the two.[]
“The idea is that the antibody helps target and deliver the drug more directly to cancer cells, where the payload is then released to damage or kill them. That doesn’t mean ADCs are free of side effects, but it does mean they are designed to damage fewer normal cells than traditional chemotherapy,” says James Hamrick, MD, MPH, Chairman of Caris Life Sciences Precision Oncology Alliance.
“There are so many new ADCs because this is where precision oncology and drug engineering are finally meeting in a very practical way,” says Dr. Hamrick. “We are getting better at identifying tumor targets, better at molecular profiling, and better at designing linkers and payloads that can make these drugs more effective.”
ADCs for solid tumors: Available this year
Dr. Hamrick points out a few of the big hitters, for solid tumors, available this year:
Datopotamab deruxtecan (Dato-DXd), used to treat EGFR-mutated non–small-cell lung cancer.[]
Trastuzumab deruxtecan (T-DXd), used to treat HER2-positive and HER2-low breast cancer; also used in HER2-expressing solid tumors.[]
Telisotuzumab vedotin (Emrelis) for previously treated, c-Met–high non-squamous non–small-cell lung cancer.[]
Trastuzumab deruxtecan (Enhertu) plus pertuzumab has moved into the first-line metastatic HER2-positive breast cancer setting.[] Dr. Hamrick calls this a “major shift in practice.”
Enfortumab vedotin for treatment of urothelial carcinoma.[]
ADCs for solid tumors in late-stage trial pipelines
Other ADCs for solid tumors are in the late-stage Phase 2 or Phase 3 trial pipelines:
Patritumab deruxtecan (HER3-DXd), for the treatment of EGFR-mutant non–small-cell lung cancer (Phase 3).[]
Ifinatamab deruxtecan (I-DXd), for the treatment of small-cell lung cancer, prostate cancer, and other solid tumors (Phase 3).[]
Sigvotatug vedotin (SGN-B6A), for the treatment of non–small-cell lung cancer (Phase 3).[]
Raludotatug deruxtecan (R-DXd), for the treatment of ovarian cancer and renal cancer; was given a Breakthrough Therapy designation (Phase 2).[]
According to Biointron,[] multiple other late-stage ADC candidates targeting HER2, TROP2, B7-H3, and Claudin18.2 in solid tumors are approaching regulatory decisions:
Ifinatamab deruxtecan (I-DXd)
Sonesitatug vedotin
Trastuzumab pamirtecan
Rinatabart sesutecan
Izalontamab brengitecan
Pivekimab sunirine
“I would say oncologists should keep an eye on investigational ADCs now in large phase 3 programs,” Dr. Hamrick says.
ADCs can still be improved upon, experts say
Despite the many ADCs currently in the pipeline, there’s still a lot of work to be done.
“There is a lot of room for improvement on current ADCs,” says Shou-Ching Tang, MD, PhD, FACP, FRCPC, Associate Dean for Translational Research and Frances Zuppardo Endowed Professor in Cancer Research at the Louisiana State University School of Medicine.
“One of the main areas of research is the development of conditionally released ADC linkers or second-generation linkers that offload the payload in the tumor microenvironment in order to increase the efficacy while reducing the systemic toxicity or off-target killing of normal cells,” adds Dr. Tang.
But that’s not all: “Other areas of improvement,” he notes, “include the antibody-binding affinity to the biomarkers, payload-to-antibody ratio, mechanism of action of payload, and presence or absence of cross-resistance to prior therapy (to avoid cross-resistance when using one ADC after another), as well as membrane permeability of payload (to increase the bystander killing of the neighboring tumor cells).”