Clinical Considerations in the Development of ADCs
By Shenggang (George) Wang, Ph.D., MSMS,
Antibody–drug conjugates (ADCs) typically consist of a monoclonal antibody (mAb) covalently attached to a cytotoxic payload via a chemical linker. ADCs combine the highly specific targeting ability of the mAb with the potent killing effect of the cytotoxic payload, achieving precise and efficient elimination of cancer cells. They have become one of the fastest-growing classes of anticancer agents.
Due to the unique structure and properties of ADCs, a successful clinical development program should consider the characteristics of all key components and their interactions (e.g., stability, pharmacokinetics, drug-to-antibody ratio). Comprehensive collaboration between clinical, clinical pharmacology, statistical, nonclinical, and CMC (chemistry, manufacturing, and controls) teams is essential for an expedited and successful clinical development program. Early engagement with regulatory agencies can help ensure alignment on development plans and facilitate a smoother path toward approval.
Clinical Considerations
From the clinical perspective, potential toxicities induced by the key components (e.g., mAb, chemical linker, cytotoxic payload) of ADCs should be considered when determining the starting dose, maximum dose, and dose escalation increments. Other key elements of the clinical study, such as inclusion and exclusion criteria, DLT criteria, safety monitoring plans, and dose modification plans, should account for these potential toxicities.
Factors like target expression levels in tumor types, the current treatment landscape, the line of therapy being targeted, and the potential benefits of the ADC compared to standard care should be thoroughly considered to maximize outcomes. For example, the development of ADCs targeting patients who are non-responders to immune checkpoint inhibitors or who have progressed after such treatments has been a significant focus area and has demonstrated promising potential. Given the increasing emphasis on dose optimization in oncology drug development, clinical studies, including first-in-human (FIH) studies, should be well-designed to meet these needs.
Clinical Pharmacology Considerations
The clinical pharmacology development programs for small molecule products and monoclonal antibodies typically diverge due to inherent differences in their physicochemical properties. However, the clinical pharmacology program of ADCs should encompass plans and assessments for both components, as ADCs combine both small molecules and biologics. Below are several critical aspects of clinical pharmacology considerations for ADCs, including but not limited to:
- The pharmacokinetics of all three crucial components should be assessed, encompassing the ADC, total antibody, released free payload, and/or any active metabolites, unless adequately justified otherwise. Bioanalytical methods should be established and validated to detect these essential components. In cases where the antibody’s target is shed into systemic circulation significantly, additional bioanalytical assays must be developed to differentiate between target-unbound ADC and target-bound ADC.
- Given the presence of the antibody component, a comprehensive assessment of anti-drug antibody (ADA) potential is crucial across CMC, nonclinical, and clinical studies. Considering the narrow therapeutic window of ADCs, it is imperative to evaluate immunogenicity and its potential impact on pharmacokinetics (PK), safety, and efficacy.
- Considering the cytotoxic payload of an ADC is a small molecule, it’s crucial to evaluate its potential for drug-drug interactions (DDIs) and the presence of any pharmacologically active metabolites. This necessitates a comprehensive assessment involving both in vitro and in vivo studies, along with careful planning for potential clinical investigations, if warranted.
- QT interval prolongation potential should also be considered, putting the right QT/QTc prolongation assessment plan as early as in the dose-escalation study is critical and strongly recommended.
- Human mass balance studies are typically not feasible to evaluate the ADME (absorption, distribution, metabolism, and excretion) properties of the ADCs. Methods to assess or predict human elimination pathways of the payload may include assessment of excreted metabolites in urine and feces in early clinical trials, or animal studies and in vitro assays of the payload.
- Due to the presence of small payload, pharmacologically active metabolites (if applicable), and/or biologics (if their molecular weight is ≤ 69 kDa), it is crucial to consider and appropriately assess the impact of organ dysfunctions (such as renal or hepatic impairment) during the development of ADCs and their constituents based on ADME properties. Unlike other drug classes, dose adjustments for ADCs are extremely challenging because the different parts of the ADC can independently affect safety and/or efficacy. For instance, if liver dysfunction increases the pharmacokinetics of the payload, leading to elevated safety risks, adjusting the dose without compromising efficacy becomes problematic. Therefore, exposure-response analyses play a vital role in selecting dosing strategies for specific subsets of patients in pivotal studies, such as those with organ impairment. Sufficient ADME information on the unconjugated payload, pharmacologically active metabolites, and/or other ADC constituents from nonclinical and early clinical studies is critical for determining the extent of organ impairment acceptable in a pivotal trial. Final dose adjustments should consider population pharmacokinetics (PopPK), data from dedicated studies on organ dysfunctions, and exposure-response analysis.
- Other intrinsic factors, including age, race, body weight, and disease state, as well as extrinsic factors like smoking status, should be considered. Their impacts can be evaluated through population pharmacokinetic analysis and/or dedicated studies.
- From a pharmacogenomics perspective, genetic variants and/or expression of the target for the antibody, genetic variants and expression levels of enzymes and transporters involved in the metabolism and elimination pathways of the payload, as well as functional genetic variants of Fc-gamma receptors (FcγRs), may contribute to influencing the pharmacokinetics, safety, and efficacy of drugs.
- Dose Optimization
The evolution of oncology drug development from traditional cytotoxic drugs to targeted therapies has rendered the historically used maximum tolerated dose (MTD) approach inadequate. This method fails to comprehensively assess low-grade symptomatic toxicities, tolerability, dosage modifications, drug activity, dose-exposure relationships, and considerations for specific populations defined by various factors such as age, organ impairment, concomitant medications, or concurrent illnesses. In response, the US FDA launched the Project Optimus Initiative to reform the dose optimization and selection paradigm in oncology drug development. This initiative recommends identifying an optimized dose based on clinical, pharmacokinetic/pharmacodynamic (PK/PD), population PK, exposure-response (ER) analysis, and nonclinical data.
In many cases, a randomized dose-finding study may be necessary, potentially causing significant delays compared to previous strategies. ADC drugs, as representatives of targeted therapies, must fully consider the need for dose optimization. Planning and executing clinical studies carefully to obtain relevant information becomes crucial in this context. For instance, incorporating a dose optimization component within the dose expansion cohorts of phase 1/2 studies has been recommended by us to sponsors as a means to address this need.
Given that ADCs consist of a small molecule payload and a targeting antibody, with payload being more cytotoxic, even a slight increase in systemic payload exposure can result in significant adverse reactions, making payload toxicity the primary safety concern. Therefore, selecting optimal dosing strategies for ADCs requires careful consideration of the differences between the pharmacokinetics (PK) and pharmacodynamics (PD) of the antibody and the payload.
Thoroughly understanding the PK/PD of not only the ADC but also its constituent parts, including any pharmacologically active metabolites, if present, early in development is crucial for optimizing the ADC dose. Gathering this critical information as early as possible in clinical studies is essential to effectively characterize safety and activity. Planning broad dose-ranging first-in-human studies and selecting multiple dose levels for evaluation in cohort expansion in Phase I or Phase II studies is highly recommended. Consideration should be given to backfilling additional patients in at least two potential dose levels in the Phase 1 escalation part to obtain additional activity/safety data before initiating dose expansion and combination cohorts.
Tolerability results, pharmacodynamic biomarkers, nonclinical findings such as receptor occupancy/target engagement data, and patient-reported outcomes (PRO) should all inform dosing strategies. Involving expertise from clinical, clinical pharmacology, statistics, nonclinical, and CMC (Chemistry, Manufacturing, and Controls) as early as possible, and utilizing modeling and simulation tools, can significantly streamline the development timeline.
Statistical Considerations
Statistical principles should be applied consistently throughout clinical development, regardless of whether designing early-phase studies, randomized studies for dose optimization, or pivotal studies for regulatory approval. While the rigor of statistical requirements may vary, pivotal studies supporting a drug’s effectiveness and safety should adhere to the FDA’s guidance on “Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products.”
Study design should be tailored on a case-by-case basis, considering factors such as indications, current standard of care (comparators), presence of unmet medical need, and others. Selection of primary endpoints, including surrogate endpoints, should also be made on a case-by-case basis.
In the case of planning multi-regional clinical trials (MRCTs), differences in standard of care among regions may lead to variations in comparators used in the studies. Therefore, the statistical plan should account for these differences.
Depending on the scientific inquiry, the endpoints observed, and the expected effect size, various study designs like single-arm, non-inferiority, superiority, or equivalence studies should be selected accordingly. This can result in significant differences in sample sizes. If a drug in development is not anticipated to outperform existing therapies, or if the improvement is marginal, alternative designs such as add-on designs may also be considered earlier.
Seamless and adaptive designs can indeed streamline drug development if planned appropriately. While these studies aim to save time or sample size, their benefits and drawbacks should be thoroughly evaluated. They typically impose stricter requirements for maintaining trial integrity. Access to comparative interim results should be restricted to individuals with relevant expertise, independent of trial personnel. A data monitoring committee (DMC) or separate committee should be responsible for making adaptation recommendations based on a carefully designed plan, excluding sponsors from such decisions. It’s crucial to fully evaluate what best suits your drug development to avoid inflating Type I error probability, as some studies may not actually save sample size.
Companion Diagnostics (CDx)
Since ADC drugs require binding to specific targets expressed on cancer cells to elicit their effects, identifying the appropriate patient population for these drugs is crucial. This may necessitate the development of a companion diagnostics tool alongside drug development if such a tool is not already available. The FDA encourages sponsors to engage with the Agency early in the development of companion diagnostics. Developing these tools in a timely manner is crucial. Meanwhile, strategically storing biological samples, including both positive and negative samples, for future validations is also necessary.
Conclusion
At ELIQUENT Life Sciences, our integrated team of professionals in clinical, clinical pharmacology, statistics, nonclinical, CMC, regulatory and devices works closely together to deliver comprehensive support, ensuring a seamless and efficient drug development program. We specialize in providing end-to-end regulatory solutions and have a demonstrated history of success, having completed over 20 ADC projects ranging from early development stages to BLA stages.
For additional information, please refer to the following guidances.
Dose Optimization
Population Pharmacokinetics (FDA)
Expose-Response Relationships – Study Design, Data Analysis and Regulatory Applications (FDA)
Clinical Pharmacology Considerations for Antibody-Drug Conjugates (FDA)
Statistical Considerations
Demonstrating Substantial Evidence of Effectiveness for Human Drug and Biological Products
Adaptive Design Clinical Trials for Drugs and Biologics Guidance for Industry