RE:RE:AstraZeneca's ADC disappoints - on severe adverse eventsMany current ADC-based treatments are associated with high discontinuation rates, especially those with the more established payload classes such as auristatins, maytansinoids and pyrrolobenzodiazepine (PBD) dimers. Another payload class that has emerged in recent years and represents a promising alternative in the treatment of several types of cancer is camptothecins. There are currently two approved camptothecin ADCs, Enhertu (trastuzumab deruxtecan) and Trodelvy (sacituzumab govitecan). While data has shown that they provide significant therapeutic benefit for patients with different types of cancer, camptothecin ADCs can present limitations and exhibit severe toxicities such as neutropenia, anemia, interstitial lung disease and gastrointestinal effects.
Emerging clinical data suggest that treatment-related off-target toxicities and maximum tolerated doses in patients are primarily related to ADC payloads. By contrast, the efficacy of ADC-based treatments, especially for solid tumors, is likely driven by a complex combination of targeted payload delivery, free payload exposure and tumor sensitivity to the molecule’s components. ADC features (including conjugation and drug-linker designs) and target expression may influence sites and rates of ADC disposition, and thus tumor, tissue and systemic exposure to the payload. It is essential that researchers consider and optimize all ADC payload properties—including the target, antibody, linker, and payload itself—to maximize clinical efficacy while balancing the risk of toxicities.
Advances in technology and improved mechanistic understanding of ADCs pave the way to optimizing their efficacy and tolerability not only in the context of monotherapy, but also as a component of combination therapy alongside complementary cancer treatments such as immunotherapy, targeted therapy and traditional chemotherapy. Ultimately, the coordinated design and optimization of ADCs holds the promise of providing unprecedented clinical benefit to patients who are unserved by existing therapeutic options, affording the best possible chance of a positive outcom.
Consequently, the addition of ONCY's biologic pelareorep as an immunotherapeutic complementary treatment will be one of the approaches to enhance the benefit of combination treatment of solid tumor cancer, with or without antibody-drug conjugate (ADC) therapy.