Antibody–drug conjugates (ADCs) and immune checkpoint inhibitors (ICIs) have transformed cancer treatment both as single agents and in combination. As ICI–ADC combinations move into earlier lines of therapy and curative-intent settings, clinicians increasingly encounter overlapping adverse events affecting the same organs. Pulmonary, hepatic, gastrointestinal and cutaneous toxicities are commonly involved, and distinguishing whether an event is immune-mediated, related to payload cytotoxicity, or driven by payload-independent ADC determinants can be difficult. The Review highlights the clinical need for standardized, mechanism-informed approaches to evaluation, acute management and decisions about treatment resumption or rechallenge.
The authors propose a three-layer framework that links distinct but interacting mechanisms to clinical toxicity:
Immune activation from ICIs or immunomodulatory effects of ADCs can produce classical immune-related adverse events affecting lung, skin, liver, colon and other organs.
Payload cytotoxicity reflects the intrinsic toxic profile of the small-molecule or cytotoxic payload released by the ADC; different payload classes generate characteristic organ-level patterns.
Payload-independent effects arise from the ADC target, antibody platform, conjugation chemistry and host-related determinants; these can cause organ-specific toxicities that are not explained by payload alone.
This layered model supports clinical reasoning about attribution and guides investigations and management in patients receiving ADC monotherapy or ICI–ADC combinations. Figures in the article illustrate the toxicity spectrum across agents and the mechanistic–clinical framework.
The Review summarizes consistent organ-level signatures associated with major payload classes. Examples highlighted include:
Interstitial lung disease and pneumonitis with deruxtecan-type payloads.
Diarrhoea and neutropenia with SN-38 payloads.
Cumulative peripheral neuropathy with monomethyl auristatin E (MMAE) payloads.
Keratopathy with monomethyl auristatin F (MMAF) payloads.
Sinusoidal obstruction syndrome with calicheamicin-containing conjugates.
Recognizing these payload-class signatures aids clinicians in distinguishing cytotoxic patterns from immune-related presentations when patients develop organ dysfunction while on ADCs or ICI–ADC combinations.
When toxicities involve organs commonly affected by both immune activation and ADC payloads (for example, lungs, skin, liver and colon), the Review recommends managing these events as immune-mediated unless a clear cytotoxic pattern predominates or can be demonstrated. For practical purposes, the authors state that when grade ≥2 toxicities occur in patients receiving an ICI–ADC combination, both agents should be held while diagnostic evaluation and initial management proceed.
The Review emphasizes a standardized clinical work-up to clarify attribution, including targeted history, examination, laboratory testing and organ-specific investigations. Imaging and tissue sampling may be required in select cases to distinguish immune-related inflammation from direct cytotoxic injury. The proposed framework is intended to reduce variability in acute management and in decisions about treatment interruption, escalation of immunosuppression and rechallenge.
To standardize care, the authors provide severity-based algorithms that address evaluation, initial management and stepwise escalation of therapy. Key principles include:
Holding both agents for grade ≥2 toxicities in ICI–ADC combinations pending assessment.
Using a graded approach to corticosteroid initiation and dosing based on toxicity severity and organ involved.
Incorporating clear thresholds for escalation to biologic agents when steroid-refractory or steroid-dependent immune-mediated toxicities are identified.
Providing auditable criteria for when and how to resume therapy, and how to approach rechallenge after toxicity resolution.
Specific dosing regimens, timelines and organ-specific pathways are presented in the Review to harmonize clinical decision-making across centers and trials.
The authors propose a minimum reporting standard to harmonize how toxicities are documented and reported in trials and clinical practice. Elements specified include:
Baseline risk assessment for relevant organs prior to initiating ADC or ICI–ADC therapy.
Structured surveillance protocols during treatment.
Uniform terminology and phenotyping of adverse events to enable cross-trial comparisons.
Detailed outcome reporting after treatment interruption and after resuming therapy, to facilitate biomarker discovery and safer regimen development.
These harmonized reporting elements aim to improve pooled analyses, pharmacovigilance and the generation of evidence-based management recommendations.
Recognizing variability in infrastructure across healthcare settings, the Review outlines resource-stratified workflows. Centres with limited access to specialized diagnostic or therapeutic resources can apply adapted surveillance and rescue strategies while still following the underlying mechanistic principles. These workflows aim to make the proposed algorithms broadly applicable and pragmatic in diverse clinical environments.
The article includes illustrative figures mapping the toxicity spectrum across ICIs and ADCs, a unified mechanistic–clinical framework, and a failure-mode map linking payload-independent ADC effects to organ-level toxicity signatures. These visual summaries support the text-based algorithms and the proposed reporting standards.
ADCs and ICI–ADC combinations present overlapping and sometimes ambiguous toxicity profiles. The Review advances a mechanism-informed framework linking immune activation, payload cytotoxicity and payload-independent determinants, emphasizes common payload-class organ signatures, and offers severity-based management algorithms and minimum reporting standards. Together, these tools are intended to standardize evaluation and management, support auditable rechallenge decisions and enable harmonized data collection to improve safety in current and future ADC-containing regimens.