# Caution: DXd ADC + agents with pneumonitis risk

Source: https://onco.cc/pairings/ild-overlap-caution/  
OnCo record `ild-overlap-caution` (Pairing). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Enhertu and its DXd cousins can inflame the lungs; combining them with immunotherapy, radiation, or mTOR inhibitors stacks that risk.

## Summary

This caution pairing concerns combining Trastuzumab deruxtecan or Datopotamab deruxtecan with agents that carry their own pneumonitis risk. These DXd ADCs can inflame the lungs, and adding immunotherapy, radiation or mTOR inhibitors stacks that risk through overlapping mechanisms that make the cause hard to attribute, as the Interstitial lung disease (ILD) / pneumonitis entry explains. ILD affects a notable minority of patients on T-DXd, checkpoint inhibitors such as Durvalumab and Pembrolizumab add a further small risk, and trials such as DESTINY-Breast07/08 and TROPION-Breast05 use careful monitoring. The evidence is toxicity data from those trials, and the pairing informs the idea of finding the lowest effective doses in a combination.

## Fields

- Kind: Pairing
- Last checked: 2026-09-04
- Pairs: Trastuzumab deruxtecan + Interstitial lung disease (ILD) / pneumonitis
- Type: caution
- Rationale: Distinct but overlapping mechanisms of pneumonitis; additive toxicity with limited ability to attribute cause.
- Evidence: Toxicity data from combination trials.

## Sources

- Powell et al., Pooled analysis of drug-related interstitial lung disease and pneumonitis in trastuzumab deruxtecan trials (ESMO Open 2022): https://doi.org/10.1016/j.esmoop.2022.100554

## Connected records

- drugs: [Datopotamab deruxtecan](https://onco.cc/drugs/datopotamab-deruxtecan/), [Durvalumab](https://onco.cc/drugs/durvalumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Trastuzumab deruxtecan](https://onco.cc/drugs/trastuzumab-deruxtecan/)
- terms: [Interstitial lung disease (ILD) / pneumonitis](https://onco.cc/terms/ild/)
- key papers: [Pooled analysis of drug-related interstitial lung disease and/or pneumonitis in nine trastuzumab deruxtecan monotherapy studies](https://onco.cc/key-papers/paper-powell-esmo-open/)
- ideas: [Find the lowest effective doses of both drugs in a combination, not the highest tolerated](https://onco.cc/ideas/idea-tr2-combo-dose-matrix/)

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