From the first-generation cytotoxic anticancer drugs to the second-generation targeted anticancer drugs and the third-generation immune anticancer drugs, anticancer drugs with various mechanisms have been developed and have played an important role in improving the survival rate of cancer patients.

Expectations for new anticancer drugs are rising, with patients often asking for good targeted or immuno-oncology drugs instead of general anticancer drugs.

Recently, antibody-drug conjugates (ADCs), the so-called fourth-generation anticancer drugs, have emerged as a new class. Antibody-drug conjugates (ADCs) are therapeutic agents that combine the properties of existing first-, second-, and third-generation anticancer drugs. ADC is a conjugate composed of three components (antibody, linker, and cytotoxic drug/payload). It is a drug with a structure where an antibody that binds to a specific target antigen on the surface of a cancer cell is conjugated to a cytotoxic drug (payload, cytotoxic anticancer drug) through a linker.

By combining the advantages of existing cytotoxic antitumor drugs and targeted antitumor drugs, it is possible to reduce the toxicity caused by high concentrations of cytotoxic antitumor drugs and increase the therapeutic effect by selectively acting by specifically recognizing cells that are abnormally overexpressed in cancer or certain diseases.

So far, 14 ADCs have been approved by the U.S. Food Drug Administration, 10 of which have been approved since 2018, and research has been very active in recent years. The two most commonly used ADCs in clinical use today are trastuzumab emtansine (Kadcyla) and trastuzumab govitecan (Enhertu), both of which target HER2 and have demonstrated efficacy and safety in HER2-positive breast cancer. In particular, Enhertu has shown impressive results in patients with HER2-positive breast cancer who have failed prior therapy, with more than a three-fold improvement in progression-free survival (PFS) compared to controls.

Enfortumab vedotin (Padcev), which targets Nectin4, is also being used in urothelial carcinoma, and a recent study showed that combination therapy with the immuno-oncology drug pembrolizumab (Keytruda) more than doubled PFS compared to conventional chemotherapy.

However, in terms of side effects, there are differences in the frequency of occurrence compared to conventional drugs, and interstitial lung disease occurred in 15 percent of patients treated with Enhertu. In the case of Padcev, the frequency of side effects of skin rash and peripheral sensory neuropathy was much higher than that of conventional cancer drugs, so careful observation is required.

As ADC drugs have been highly successful in clinical trials, global pharmaceutical companies are rushing to develop them, and clinical studies have been conducted in various cancers that share the same target, showing good results.

Besides, second and third-generation ADCs that have overcome the side effects of first-generation ADCs have been developed and are undergoing clinical trials. Combined therapy with other anticancer drugs, such as immuno-oncology drugs, also shows good results.

Side effects also differ from existing therapies, and appropriate responses are needed. The discovery of new antibodies, drugs that reduce toxicity and increase effectiveness, and the development of linkers that efficiently release therapeutic agents are continuously needed.

Professor Jo Jeong-min graduated from Pusan National University College of Medicine and trained in internal medicine at Asan Medical Center, and is an associate professor of the Department of Hematology/Oncology at Ewha Womans University Mokdong Hospital, where she treats urinary, colorectal, biliary, and pancreatic cancers. She is a member of the Korean Cancer Society, the Korean Society of Medical Oncology, and the Society for the Study of Chemotherapy. She is an active member of the Korean Society of Medical Oncology Public Relations Committee.