This Executive Summary captures the key takeaways from a recent webinar I moderated titled “ADCs in Oncology Trials: Practical Strategies for Clinical Development Success.” The session featured a panel of industry experts who shared insights into the evolving landscape of antibody-drug conjugates (ADCs) and the practical strategies needed to navigate clinical development successfully.
ADCs are redefining cancer therapy by combining the targeting precision of monoclonal antibodies with the cancer-killing potency of cytotoxic drugs or other payloads. This approach enables selective destruction of cancer cells while minimizing damage to healthy tissue. Fueled by advances in antibody engineering, linker chemistry, and payload innovation, ADCs have surged to the forefront of oncology R&D.
The webinar explored the scientific, regulatory, and operational complexities of ADC trials, offering practical guidance for sponsors and clinical teams. Below are the key takeaways from the discussion.
Key Takeaway 1: ADC science ─ technology evolution
Antibody-drug conjugates (ADCs) are rapidly evolving through breakthroughs in antibody targeting, linker chemistry, and payload design—each element playing a critical role in shaping the therapeutic performance and safety profile of the drug.
- Enhanced antibody targeting and smarter linker designs allow ADCs to selectively attack tumor cells while minimizing harm to healthy tissue—improving both efficacy and tolerability.
- Shift to newer payloads like topoisomerase inhibitors (e.g. SN-38) offer broader applicability and better safety profiles compared to earlier payloads like auristatins (e.g. MMAF), enabling treatment of more tumor types with fewer side effects.
- Stable linkers and the bystander effect help ADCs reach heterogeneous tumors, increasing therapeutic impact even in cancers with variable antigen expression.
- Advances in drug-antibody ratio (DAR) and site-specific conjugation improve consistency, pharmacokinetics, and tumor penetration—resulting in more predictable and potent therapies.
- Biparatopic, bispecific, and dual-payload ADCs are being developed to overcome resistance and target multiple antigens, offering new solutions for complex and refractory tumors.
These scientific advances are not only improving ADC performance but also enabling sponsors to differentiate their therapies in a competitive landscape through smarter design and strategic innovation.
Key Takeaway 2: Regulatory and protocol design considerations
Designing ADC trials requires a strategic and adaptive approach to meet evolving regulatory expectations while maximizing clinical success.
Tailored trial designs
Custom protocols for both early-phase and registrational studies allow sponsors to align trial objectives with the unique pharmacology and toxicity profiles of ADCs—improving data relevance and regulatory confidence.
Proactive regulatory alignment
Engaging early with regulators and addressing toxicity management, dose justification, and biomarker strategy in pre-IND/IND submissions helps streamline approvals and reduce delays.
Smarter dose selection
Under FDA’s Project Optimus, sponsors are shifting from fixed-dose models to data-driven dose optimization—balancing efficacy and safety through robust PK/PD analysis and modeling.
Anticipating toxicity challenges
Protocols that proactively address common ADC payload-related toxicities (e.g. neurologic or ocular for tubulin inhibitors or hepatic, hematologic and pulmonary for DNA-damaging agents) enable better patient safety and smoother regulatory review.
By embracing adaptive design principles and regulatory foresight, sponsors can accelerate development timelines and improve the likelihood of approval in a competitive ADC landscape.
Key Takeaway 3: Biomarker-driven recruitment and cohort management
Biomarker strategies are unlocking more precise and effective ADC trials, but they require thoughtful execution.
- Targeted enrollment: Stratifying patients by biomarker-defined cohorts enables more accurate efficacy and safety assessments, improving trial outcomes and regulatory confidence.
- Operational efficiency: Validated assays and streamlined screening protocols help accelerate recruitment and reduce delays, especially in trials with narrow eligibility criteria.
- Adaptive flexibility: Cohort expansion strategies allow sponsors to respond quickly to emerging data, optimizing enrollment and accelerating go/no-go decisions.
Key Takeaway 4: Safety and toxicity management
Managing ADC toxicity is essential to protect patients and preserve therapeutic potential.
Proactive risk mitigation
Early identification and management of common toxicities associated with your payload—such as ocular events, peripheral neuropathy, or hematologic effects—help maintain patient safety and trial continuity.
Empowered sites
Training investigators to recognize ADC-specific adverse events ensures timely intervention and builds site confidence in handling complex protocols.
Patient-centric protocols
Incorporating dose reduction or dose delay guidance, supportive care/prophylactic measures, and patient education into trial design reduces dropout rates and improves overall treatment tolerability.
Key Takeaway 5: Drug resistance and adaptive strategies
Innovative trial designs and combination approaches are helping ADCs overcome resistance and extend durability.
- Multi-mechanism targeting: Dual-payload and bispecific ADCs are being developed to counter antigen escape and tumor heterogeneity, improving response rates in challenging indications.
- Strategic combinations: Pairing ADCs with checkpoint or kinase inhibitors may enhance efficacy and delay resistance, offering new therapeutic synergies.
- Responsive design: Basket and umbrella trials provide flexible frameworks to test multiple strategies, while longitudinal biomarker monitoring enables timely treatment adjustments.
Key Takeaway 6: Global operational strategy and feasibility planning
Global expansion and strategic planning are critical to accelerating ADC trial execution.
- Broader reach: Sponsors are expanding outside of North America into Europe, Asia, and Latin America to boost enrollment and diversify patient populations.
- Smarter site selection: Leveraging networks with ADC experience and conducting feasibility assessments ensures faster activation and fewer protocol deviations.
- Regulatory alignment: Early engagement with authorities in key markets helps streamline approvals and avoid costly delays, while contingency planning supports complex ADC supply chains.
In Conclusion
Antibody-drug conjugates are rapidly becoming a cornerstone of precision oncology, offering a powerful combination of targeted delivery and potent cytotoxicity. As discussed during the webinar, the path to successful ADC development is complex—requiring innovation in antibody, linker, and payload design, as well as thoughtful clinical trial execution.
From regulatory shifts like Project Optimus to operational challenges such as biomarker-driven recruitment and toxicity management, sponsors must navigate a dynamic and competitive landscape. However, with strategic planning, adaptive trial designs, and cross-functional collaboration, the potential of ADCs to transform cancer care is within reach.
The insights shared in this session underscore the importance of staying ahead of scientific and regulatory trends to bring these promising therapies to patients faster and more effectively.
Ready to accelerate your ADC therapy program?
Contact Catalyst Oncology today for a strategic consultation and discover how our expertise can drive your trial forward.
