Hyunji Kim, a breast cancer patient, has found renewed hope through the experimental antibody-drug conjugate (ADC) LCB84 after facing limited success with previous treatments like Trodelvy. ADCs are emerging as a significant advancement in cancer therapy, offering targeted delivery of cytotoxic agents directly to cancer cells, thereby minimizing systemic toxicity.
The Promise of Antibody-Drug Conjugates
Dr. Yuan Yuan from Cedars-Sinai Medical Center describes ADCs as "designer drugs" that combine a target-specific antibody with a chemotherapy payload. This approach allows for cancer cell-specific delivery, reducing the impact on healthy tissues. The antibody targets receptors like HER2 or TROP2 on cancer cells, and once the ADC is internalized, the cytotoxic drug is released, killing the cell and potentially affecting neighboring cells through a 'bystander effect'.
Clinical Landscape and Ongoing Research
Currently, over 150 ADCs are in clinical trials across various cancer types. LCB84, targeting TROP2, is being evaluated in a phase 1/2 trial, both as a monotherapy and in combination with Keytruda, for solid tumors including breast cancer. Nancy Lin from Dana-Farber Cancer Institute highlights the modular nature of ADCs, where modifications to the target and chemotherapy payload can create numerous potential combinations.
Approved ADCs and Shifting Treatment Paradigms
Several ADCs have already gained FDA approval for breast cancer treatment, including Kadcyla, Enhertu, and Trodelvy. Erika Hamilton from Sarah Cannon Research Institute notes that ADCs have consistently outperformed single-agent chemotherapy in metastatic breast cancer trials. Notably, Enhertu has shown efficacy even in tumors with low HER2 expression, challenging previous assumptions about target expression levels. Trodelvy, a TROP2-targeting ADC, has demonstrated efficacy regardless of TROP2 expression levels.
Important Considerations for Clinical Use
Despite the excitement surrounding ADCs, experts emphasize the importance of recognizing their distinct side effect profiles. For example, Kadcyla is not associated with hair loss but can cause low platelet counts, while Enhertu can cause nausea, hair loss, and interstitial lung disease (ILD) in 10-15% of patients. Trodelvy's prominent side effects include neutropenia and diarrhea. Therefore, careful consideration of individual patient factors is crucial when selecting an ADC.
The Future of ADC Therapy
Researchers are actively exploring the optimal sequencing and combination strategies for ADCs. Yuan emphasizes the need for more data to guide treatment decisions in the clinical setting. Hamilton concludes that the possibilities for new ADC development are "endless," with ongoing research focused on different payloads and antibody targets, suggesting a continued expansion of ADC options in the future.
