Safety of combining radiotherapy and antibody drug conjugates in advanced urothelial and other cancers.
Authors: Lock Derrick , Soni Yash , Hwang Lindsay , Cole Suzanne , D'souza Anishka , Garant Aurelie , Yang Daniel X. , Arafat Waddah , Zhang Tian , Ballas Leslie K. , Desai Neil B 
Published: February 2025

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Background:
Antibody drug conjugates (ADCs) such as enfortumab vedotin (EV) and sacituzumab govitecan (SG) are novel treatments increasingly used for metastatic urothelial carcinoma (mUC). SG is also utilized in metastatic breast cancer (mBC). Radiotherapy (RT) is used for palliation or consolidation of metastatic sites in mUC and for bladder preservation in localized disease. There is limited data evaluating the safety of ADCs when combined with RT. We sought to characterize the safety of RT in patients with mUC or mBC cancer receiving EV or SG.
Methods:
A bi-institutional retrospective analysis was performed. Eligible patients had a diagnosis of mUC or mBC and received RT within 6 months of EV or SG receipt. Patients were stratified by intensity of RT (higher vs. lower), site of RT (pelvis with bladder, pelvis without bladder, outside pelvis), and RT timing relative to ADC (prior to, within 4 weeks of, or after ADC infusion). ADC status was categorized as discontinued for progression of disease, discontinued for toxicity, or continued therapy. Those who discontinued ADC for toxicity were further evaluated to assess attribution to RT vs. expected treatment-limited toxicity of ADC.
Results:
Between January 1, 2020 and January 31, 2024, 103 patients received 166 RT courses within 6 months of ADC. RT courses were of mostly lower intensity (66%) vs. higher intensity (34%), using a cutoff of biologically equivalent dose (a/b=10) of 35Gy after assessing the distribution of RT regimens. RT location was extra-pelvic (58%), pelvis without bladder (16%), brain (14%), and pelvis with bladder (11%). RT delivery occurred prior to ADC (30%), concurrent with ADC (46%), or after ADC completion (24%). Of 77 RT courses concurrent with ADC, 10 (13%) patients experienced grade 3-5 toxicity. All of these were attributed to known ADC toxicities and only one possibly influenced by addition of RT. No patients receiving RT to the bladder experienced high-grade toxicity.
Conclusions:
This real world, retrospective study thus found no added safety events for patients receiving RT with ADCs, even when administered concurrently. Further data to validate these findings is needed as the use of both ADCs and RT increases in patients with urothelial carcinoma.

Concurrent ADC–RT and toxicity.

Patient #
Toxicity Grade
Toxicity History
Relationship to RT

1
G3 skin
Out of RT field
Unlikely

2
G3 neuropathy
Out of RT field
Unlikely

3
G3 neuropathy
Out of RT field
Unlikely

4
G3 neuropathy
Out of RT field
Unlikely

5
G3 neuropathy
Out of RT field
Unlikely

6
G3 pneumonitis
Out of RT field
Unlikely

7
G3 skin
Out of RT field
Unlikely

8
G3 thrombocytopenia
Began prior to RT
Unlikely

9
G3 oral mucositis
Out of RT field
Unlikely

10
G5 neutropenia vs. pneumonitis
1 week after completing craniospinal irradiation, ADC infusions resumed; two weeks later, the patient was admitted for pneumonia
Possible

ADC: Antibody-drug conjugate; RT: Radiotherapy.