How ADCs are changing the treatment of cancer

Antibody-drug conjugates (ADCs) represent a transformative class of cancer therapy that combine the targeting ability of antibodies with the cell-killing potential of cytotoxic drugs.

Surging in popularity, these "smart bombs" deliver potent drugs directly to cancer cells, minimizing harm to healthy tissue - but their journey has been filled with challenges.

Now, as the global oncology market continues to expand, how are ADCs poised for greater growth, and what new advancements might help this approach to push into a wider array of cancers?

Broad pipeline

The breadth of the current pipeline for ADCs is one of the most exciting aspects of their development. Over 260 ADC candidates are in various stages of clinical trials, spanning a wide array of indications, from breast and lung cancers to blood cancers.

Late-stage candidates include datopotamab deruxtecan from Daiichi Sankyo (TSE: 4568) and AstraZeneca (LSE: AZN), which is currently in Phase III trials for breast and non-small cell lung cancers (NSCLC).

Additionally, Teliso-V (telisotuzumab vedotin) from AbbVie (NYSE: ABBV) targets NSCLC, while Syvli (trastuzumab duocarmazine) from Byondis is advancing toward approval for HER2-positive breast cancer.

In the mid-stage pipeline, ladiratuzumab vedotin from Merck (NYSE: MRK) and Seagen is being explored for breast, head and neck, and other cancers. Camidanlumab tesirine from ADC Therapeutics (NYSE: ADCT) and Genmab holds promise for treating Hodgkin lymphoma, while IMGC936 from ImmunoGen (Nasdaq: IMGN) and MacroGenics (Nasdaq: MGNX) is in trials for solid tumors, including colorectal and pancreatic cancers.

Early-stage candidates, like PRO1107 by ProfoundBio, which targets ovarian and endometrial cancers, and other emerging therapies, demonstrate the diversity of therapeutic targets within the ADC pipeline.

Biggest impact

So far, ADCs have demonstrated the most significant efficacy in particular cancers, particularly HER2-positive breast cancer and blood cancers.

Kadcyla (trastuzumab emtansine), one of the first ADCs targeting HER2, transformed the treatment landscape for HER2-positive breast cancer by reducing systemic toxicity while delivering potent anti-cancer agents.

Its successor, Enhertu (trastuzumab deruxtecan), has further pushed the boundaries, expanding into HER2-low breast cancer and showing promising results in lung and gastric cancers.

In blood cancer, ADCs like Adcetris (brentuximab vedotin), which targets CD30-positive malignancies, have achieved high response rates in Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL).

Meanwhile, Mylotarg (gemtuzumab ozogamicin) has carved out a niche in treating certain forms of acute myeloid leukemia (AML). These successes illustrate how ADCs have become indispensable tools in the oncologist's arsenal, particularly for difficult-to-treat cancers that express specific markers like HER2, CD30, or CD33.

Ongoing challenges

Despite their promise, ADCs have faced numerous challenges. One of the primary difficulties is balancing efficacy with toxicity, caused by off-target effects.

For example, datopotamab deruxtecan in combination with chemo has led to serious adverse events, including nausea, fatigue, and neutropenia. Similarly, mirvetuximab soravtansine, used for platinum-resistant ovarian cancer, has been associated with eye problems, diarrhea, and other significant side effects.

Another major challenge is improving efficacy in solid tumors. While ADCs have been highly effective in blood cancers, solid tumors pose additional hurdles, such as poor penetration of the tumor mass, among other things.

Many solid tumors do not express high levels of a single, easily targetable antigen, something which is important for effective treatment. There is also the so-called "bystander effect," where the cytotoxic agent kills both cancerous and nearby healthy cells.

Manufacturing complexity has also remained a hurdle, with ADCs requiring precise engineering to link the antibody and cytotoxic payload securely, demanding advanced manufacturing technologies - inevitably leading to higher costs and increased regulatory challenges.

Market outlook

The ADC market has attracted intense competition from major pharmaceutical companies, including Merck (NYSE: MRK), Pfizer (NYSE: PFE), and Gilead Sciences (Nasdaq: GILD), all of which are now heavily investing in ADC research and development.

As the market matures and clinical challenges continue to be met, ADC revenues have expanded. Current global revenues are estimated to grow from $10 billion at present to nearly $30 billion by 2028.

Leading the commercial landscape is Enhertu, which reported a staggering $2.5 billion in sales in 2023, more than doubling its revenue from the previous year. Kadcyla continues to perform well in the HER2 space, with 2023 sales surpassing $2.2 billion.

In addition to breast cancer, ADCs like Trodelvy (sacituzumab govitecan) are being deployed against triple-negative breast cancer and urothelial cancer, with sales exceeding $1 billion in 2023.

Roche's (ROG: SIX) Polivy (polatuzumab vedotin) and Seagen’s Tivdak (tisotumab vedotin) are also making significant strides in the treatment of lymphoma and cervical cancer, respectively.

Future direction

Innovations in linker technology and dual-drug ADCs are promising avenues to increase efficacy and reduce toxicity.

CanWell Pharma is one good example, the privately-held Chinese firm leading in the development of a next-generation linker platform called StarLinker, which allows the attachment of multiple therapeutic agents to a single ADC.

If developers can boost the drug-to-antibody ratio they can enhance the potency of the therapy, while minimizing off-target effects.

Combination therapies offer another path for improvement, with ADCs being paired with immunotherapy or radiotherapy - early trials have shown promise for better efficacy and safety.

And there may be a lot more to get excited about. While their initial application has naturally been in the area of cancer, researchers are also exploring whether autoimmune diseases - another gigantic market - could be amenable to treatment with this approach.