Antibody-drug conjugates (ADCs) are crucial aspects of chemotherapy, aiding in the enhancement of treatment for patients with breast cancer (BC). At the 2024 San Antonio Breast Cancer Symposium in San Antonio, Texas, experts offered insights into the development and evolution of ADCs, highlighting the clinical impact of these agents in breast cancer, as well as addressing challenges in sequencing, toxicities, and biomarker identification to personalize treatment and ongoing research. Their discussion examined the notable applications of trastuzumab deruxtecan (T-DXd, Enhertu; Daiichi Sankyo) and trastuzumab emtansine (T-DM1, Kadcyla; Genentech), across BC subtypes, including HER2-positive (HER2+) and HER2-negative (HER2-) cases, with a focus on their use in metastatic disease and the clinical impact of these agents.1
ADC wooden blocks and stethoscope | Image Credit: © surasak - stock.adobe.com
What are ADCs?
ADCs are targeted therapies that combine a monoclonal antibody (mAb) with a cytotoxic drug with the goal of increasing the therapeutic window by specifically delivering the toxic payload to tumor cells while minimizing systemic toxicity. The concept dates back to the late 1800s when Paul Ehrlich envisioned the concept of a “magic bullet” using an antibody to selectively deliver a toxic agent. Over a century later in the 1960s, chemotherapy agents were conjugated to IgG fractions, but the invention of monoclonal antibodies in the 1980s provided the selective binding needed to precisely target specific antigens on cancer cells, minimizing damage to healthy tissues and enhancing the efficacy of therapeutic agents.
In the 1980s, the need for highly potent payloads became clear as the first generation of ADCs were developed. Through symmetry studies and radiolabeled antibodies, researchers measured how much of the injected ADC ended up in the tumor and found that typically only about 1% of the injected dose per gram of tumor accumulated, with a peak around 1 day after IV administration. This led to the need for highly potent payloads capable of overcoming the limited tumor accumulation of ADCs. Additionally, the first ADCs used mAbs that were found to be immunogenic; however, this was later resolved through the development of fully human antibodies.
The FDA approval of the first ADC took 20 years, with gemtuzumab ozogamicin (Mylotarg; Pfizer for Professionals) in 2000 for patients aged over 60 with CD33-positive acute myeloid leukemia. However, it was withdrawn from the market in 2010 due to a lack of clinical benefit and high fatal toxicity rate compared to the standard chemotherapy. Despite earlier setbacks, innovations in ADCs continued, leading to the development of 11 FDA-approved agents by 2021. Notably, T-DM1 became the first ADC to receive full FDA approval in 2013 based on data from the EMILIA trial (NCT00829166).2
“After 10 years on the market, Pfizer withdrew [gemtuzumab ozogamicin] from the market after a failed phase 3 trial,” explained John Lambert, PhD, owner of John Lambert Consulting in Cambridge, Massachusetts. “And in truth, this ADC was really very toxic. It didn't have the properties that would lend itself to being able to treat solid tumors.”
The mechanism of action of ADCs involves the binding of the antibody component to a tumor-associated antigen on the surface of cancer cells. The antibody component aids in selective targeting of the tumor while the cytotoxic drug payload is responsible for inducing apoptosis of cancer cells. Once the ADC attaches, it is internalized into an endosome within the cell, triggering the degradation of the antibody and linker, and thereby releasing the cytotoxic drug payload. The payload, now released, can enact cytotoxic effects and apoptosis of the cancer cells, potentially leading to a bystander effect on neighboring cells.
Concept of cell undergoing apoptosis | Image Credit: © BURIN93 stock.adobe.com
There are multiple potential mechanisms of resistance underlying ADCs based on their design features, and resistance can either be antibody- or payload-related. Antibody-related mechanisms can include the loss or downregulation of the target antigen on the tumor cells or trafficking alterations that reduce delivery of the agent to the lysosome. Payload-related resistance mechanisms, similar to what is typically seen with traditional chemotherapy, include drug efflux pumps or alterations in the drug target.
“So current ADCs are essentially single-agent chemotherapy, and so the most likely mechanism resistance in general is that ‘halo’ of resistance mechanisms common to classic chemotherapy,” Lambert said. The nature of the linker connecting the antibody to the drug also plays a crucial role in resistance mechanisms. In ADCs with cleavable linkers and diffusible payloads, the resistance is more likely to be driven by payload resistance, such as drug efflux pumps or alterations in the drug target. Conversely, resistance mechanisms in ADCs with non-cleavable linkers may be more dependent on mechanisms that interfere with trafficking of the ADC to the lysosome, where the payload needs to be released.
The Art of ADC Development
“We really do acknowledge that ADCs bring a novelty compared to what chemotherapy can bring,” said Ingrid Mayer, global clinical strategy head for Breast and Gynaecological Cancers, R&D leading clinical development for AstraZeneca. “But the stars have to align correctly for ADCs to work. You need to have a great target, you need to have a great linker, and you need to have internalization—hopefully, if you're lucky get bystander effect. Hopefully, you can develop some immunogenicity in the tumor microenvironment, which is very conducive for combinations with immunotherapy.”
A deep understanding of the disease biology and performance characteristics of ADC components are necessary for development and aid researchers in matching the right drugs to the right patients. It also optimizes their therapeutic index and helps overcome resistance mechanisms. Mayer pointed to 3 key considerations in ADC development: target selection, conjugation, and payloads.
Target selection involves multiple considerations including understanding the target’s surface protein density, evaluating its internalization potential, and assessing its heterogeneity of expression for bystander effects. Conjugation is concerned with the drug-antibody ratio and site-specific conjugation, which are important considerations in ADC development, as they can impact the stability and toxicity profile of the agent. Payload considerations are also necessary, and exploring new payloads such as innate immune agonists, DNA repair inhibitors, and epigenetic modifiers may provide opportunities for sequencing ADCs.
A key innovation was the use of tubulin-binding agents as payloads, which proved to be stable and potent. This led to the development of brentuximab vedotin (Adcetris; Pfizer), an anti-CD30 ADC that entered the clinic in 2006. Lambert also pointed to T-DM1, another ADC utilizing tubulin-binding agents that was approved by the FDA to treat women with MBC. However, Mayer admitted there are still challenges that need to be addressed.
Antibody drug conjugate illustration | Image Credit: © huenstructurebio.com - stock.adobe.com
“Microtubule inhibitors, unfortunately, are associated with neuropathy as one of their limiting side effects,” she said. “Therefore, exploring new payloads, such as innate immune agonists, PROTACs, DDR inhibitors, epigenetic modifiers, or sub-death inhibitors, could offer promising alternatives. These payloads could enable the sequencing of ADCs in a highly efficient way, maintaining superior efficacy compared to chemotherapy while avoiding the reuse of the same payloads.”
Challenges with ADCs
Similar to any other therapeutic agent, ADCs have challenges that interfere with patient outcomes, including difficulties in optimizing sequencing, managing toxicities, and identifying reliable biomarkers to guide treatment. Addressing these challenges requires continued innovation in ADC design, the development of more comprehensive toxicity profiles, and the creation of robust biomarkers to optimize therapeutic strategies.
Understanding the optimal sequencing of different ADCs is crucial for overcoming the development of resistance mechanisms that limit the efficacy of subsequent ADC treatments, which can occur even when targeting the same antigen. According to prospective trial data, the median progression-free survival (PFS) with a second ADC was often shorter compared to the first. This suggests the potential development of mutations in the target antigen or alterations in the enzymes metabolizing the payload, making the tumor less responsive to subsequent ADC treatment. Thereby, Mayer suggested that sequencing ADCs with different payloads may be one approach to overcoming these challenges in both HER2+/HER2-low disease settings.
Managing ADC toxicity is a multi-faceted challenge that requires consideration of patient factors, prior therapies, target expression, payload properties, and pharmacogenomic profiles. On-target and payload-related toxicities contribute to various adverse effects including on-target toxicity related to the normal tissue expression of the target antigen, as well as neuropathy, gastrointestinal symptoms, and fatigue, respectively. There is also the potential obstacle of catabolism and off-target toxicity. Additionally, as seen in the ASCENT trial (NCT02574455), genetic polymorphisms, such as in the UGT1A1 gene, can impact the pharmacokinetics and toxicity of ADCs.3
Breast cancer cell | Image Credit: © Jack - stock.adobe.com
Target antigen expression can be a key biomarker to predict treatment response, and precise measurements coupled with an understanding of the relationship between target antigen levels and ADC activity are crucial for optimizing therapeutic strategies and improving patient outcomes.
“Given the concurrent development of multiple agents, the best ADC sequencing, in my opinion, remains unclear, and we need to design new clinical trials of sequencing,” said Giuseppe Curigliano, MD, PhD, professor of medical oncology at the University of Milan, and chief of the Division of Early Drug Development at the European Institute of Oncology in Milan, Italy. “Biomarkers of resistance and activity are needed to personalize treatment. Effective toxicity prevention monitoring and management are essential to maximize the risk-benefit ratio.”
ADCs in Clinical Practice
Antibody-drug conjugates (ADCs) such as trastuzumab deruxtecan (T-DXd) and trastuzumab emtansine (T-DM1), along with emerging agents like sacituzumab govitecan-hzi (Trodelvy; Gilead Sciences, Inc.) and patritumab deruxtecan (U3-1402; Merck), have demonstrated promising results in improving patient outcomes and reshaping treatment for metastatic breast cancer (MBC) across HER2-positive, HER2-negative, and triple-negative disease subtypes.
Key trial data, including the DESTINY-Breast03 (NCT03529110) and DESTINY-Breast06 (NCT04494425) trials, showed significant improvements in progression-free survival (PFS) with T-DXd: 28 months for HER2-positive MBC and 14 months for HER2-negative metastatic disease. Real-world studies like DESTINY-Breast12 (NCT04739761) further highlighted its efficacy. In the randomized phase 3 EMILIA trial, T-DM1 demonstrated a longer PFS compared with lapatinib plus capecitabine (9.6 months vs. 6.4 months) and improved overall survival (29.9 months vs. 25.9 months), playing a key role in securing FDA approval and defining its role in the treatment landscape.4-6
Emerging agents are also showing promise, with patritumab deruxtecan achieving a 53% response rate and a 7-month PFS in the ICARUS BREAST01 trial (NCT02980341), and sacituzumab govitecan-hzi demonstrating improvements in median PFS in the TROPICS-02 trial (NCT03901339). These findings underscore the transformative potential of ADCs in MBC treatment, setting the stage for future innovations that could refine and expand their applications.7,8
Future Directions
The future of antibody-drug conjugates (ADCs) holds significant promise, driven by ongoing research and innovation aimed at broadening their applications across various cancer types. The integration of bispecific technologies, which allow ADCs to target multiple antigens simultaneously, is expected to enhance their precision and efficacy. Site-specific linking is also a key strategy for improving drug stability and delivery, ensuring ADCs reach their intended targets more effectively while minimizing off-target effects.
Innovations in payload design, such as the development of novel payloads tailored to specific tumor characteristics, will further refine the therapeutic index of ADCs. These advances could revolutionize cancer treatment by enabling ADCs to selectively release therapeutic agents within the tumor microenvironment, thus reducing systemic toxicity and enhancing patient outcomes. As the landscape of ADC development continues to evolve, their role in personalized cancer therapy is set to expand, making them an increasingly central component in the fight against cancer.
REFERENCES
1. Tarantino P, Lambert J, Mayer I, et al. Educational session 7: people's choice – future directions in antibody drug conjugates. Presented at: 2024 San Antonio Breast Cancer Symposium. December 11, 2024. San Antonio, TX.
2. A study of trastuzumab emtansine versus capecitabine + lapatinib in participants with HER2-positive locally advanced or metastatic breast cancer (EMILIA). ClinicalTrials.gov Identifier: NCT00829166. Updated October 31, 2024. Accessed December 11, 2024. https://clinicaltrials.gov/study/NCT00829166
3. Trial of sacituzumab govitecan in participants with refractory/relapsed metastatic triple-negative breast cancer (TNBC) (ASCENT). ClinicalTrials.gov Identifier: NCT02574455. Updated June 15, 2022. Accessed December 11, 2024. https://clinicaltrials.gov/study/NCT02574455
4. DS-8201a versus T-DM1 for human epidermal growth factor receptor 2 (HER2)-positive, unresectable and/or metastatic breast cancer previously treated with trastuzumab and taxane [DESTINY-Breast03]. ClinicalTrials.gov Identifier: NCT03529110. Updated June 12, 2024. Accessed December 11, 2024. https://clinicaltrials.gov/study/NCT03529110
5. Study of trastuzumab deruxtecan (T-DXd) vs investigator's choice chemotherapy in HER2-low, hormone receptor positive, metastatic breast cancer (DB-06). ClinicalTrials.gov Identifier: NCT04494425. Updated October 10, 2024. Accessed December 11, 2024. https://clinicaltrials.gov/study/NCT04494425
6. A study of T-DXd in participants with or without brain metastasis who have previously treated advanced or metastatic HER2 positive breast cancer (DESTINY-B12). ClinicalTrials.gov Identifier: NCT04739761. Updated October 23, 2024. Accessed December 11, 2024. https://clinicaltrials.gov/study/NCT04739761
7. Phase i/ii study of U3-1402in subjects with human epidermal growth factor receptor 3 (HER3) positive metastatic breast cancer. ClinicalTrials.gov Identifier: NCT02980341. Updated October 30, 2024. Accessed December 11, 2024. https://www.clinicaltrials.gov/study/NCT02980341
8. Study of sacituzumab govitecan-hziy versus treatment of physician's choice in participants with HR+/HER2- metastatic breast cancer (TROPiCS-02). ClinicalTrials.gov Identifier: NCT03901339. Updated October 21, 2024. Accessed December 11, 2024. https://clinicaltrials.gov/study/NCT03901339