ASCO GU 2025: Overcoming Challenges of Antibody Drug Conjugate Toxicity in Bladder Cancer

(UroToday.com) The 2025 GU ASCO annual meeting featured a session on the ABCs of antibody drug conjugates and a presentation by Dr. Daniel Castellano discussing overcoming the challenges of antibody drug conjugate toxicity in bladder cancer. Dr. Castellano started his presentation by reviewing the categorization of adverse events by grade using the CTCAE, with grade referring to the severity of the adverse event:

It is important to note that the most common toxicities related to antibody drug conjugates are associated with payload classes:

The current advanced urothelial carcinoma antibody drug conjugates and targets include:

• Nectin-4: enfortumab vedotin
• Trop-2: sacituzumab govitecan
• HER-2: disitamab vedotin
• HER-2: trastuzumab deruxtecan 

With regards to enfortumab vedotin, the most common toxicities are secondary to the MMAE payload. This includes skin toxicity through the delivery of MMAE into Nectin-4 expressing normal tissue, such as the epidermis and epithelium of sweat glands and hair follicles. Histopathology shows vacuolar interface dermatitis (erythema or hyperpigmentation). Severe cutaneous adverse reactions vary in terms of mortality rate and systemic involvement such as SJS and TEN (which has the highest mortality rate). The typical onset of skin toxicity is 1.7 months after starting treatment and in clinical studies, 55% of patients develop skin reactions. Of these, 13% of patients develop severe (grade 3 or 4) skin reactions, and 3.8% develop serious skin reactions:

Dr. Castellano’s recommendations for management of skin toxicity by grade are as follows:

• Grade 3: interrupt enfortumab vedotin until grade <= 1 and then resume treatment at the same dose level or consider dose reduction by one dose level. Oral corticosteroids (ie. prednisone 0.5 mg/kg/day or equivalent) can be given for 14 days. Patients should be considered for a dermatologic consultation
• Grade 4 or recurrent Grade 3: discontinue enfortumab vedotin. Inpatient management for specialized care with dermatologic consultation as appropriate
• Suspected SJS/TEN: immediately withhold enfortumab vedotin and consider dermatologic consultation. Biopsy of multiple sites 

Peripheral neuropathy is also a common side effect of enfortumab vedotin and is associated with tubulin polymerization secondary to the MMAE payload. MMAE binds to different sites along the length of microtubules, resulting in the onset of peripheral neuropathy. Peripheral neuropathy is a complex disorder characterized by sensory, motor, and autonomic dysfunction. Sensory symptoms typically present as partial paresthesia/pain in the feet and hands, motor and abnormal autonomic symptoms are relatively infrequent. The onset is typically 6 months after starting treatment and in clinical studies ~50% of patients developed peripheral neuropathy, leading to a dose reduction in 30% of patients and permanent discontinuation in 10% of patients.

The mechanism of how enfortumab vedotin causes insulin resistance and diabetic ketoacidosis is not well understood (onset is typically 0.5 months after starting treatment). The timing and onset of enfortumab vedotin-related diabetic ketoacidosis varies significantly but has been reported to occur 3 days after the second dose. Various mechanisms may lead to off-target effects of enfortumab vedotin: (i) relatively unstable cleavable linkers can result in premature deconjugation of MMAE in the plasma, and (ii) the “bystander effect” where the payload is then able to diffuse back into the extracellular space and surrounding cells. For hyperglycemia in the context of enfortumab vedotin, the key is prevention and education:

Based on work Dr. Petrylak presented at ASCO 2024 looking at dose adjustment and efficacy of enfortumab vedotin, most patients will dose reduce enfortumab vedotin by cycle 8, and durable responses are maintained with enfortumab vedotin despite dose modifications in EV-301:¹

In EV-302,² the most common toxicities were again related to the MMAE payload, with risk of overlapping toxicity with checkpoint inhibitors, which can typically cause skin toxicity, diarrhea, and pneumonitis. However, in EV-302, the safety of pembrolizumab was consistent with previously observed results. Dr. Castellano notes that in EV-302 there are patients with a large exposure of enfortumab vedotin + pembrolizumab for responding patients (given the objective response rate of 67.7%). This may lead to an increased risk of cumulative grade 2 or 3 toxicity, which means it may be prudent to consider de-escalation dose strategies. But, who may benefit from a de-escalation strategy remains uncertain: only for patients with a tumor complete response or maintained partial response? Patients with a large treatment exposure above the estimated median progression free survival of 12.5 months? Moreover, is the cumulative toxicity of grade 3-4 toxicity a good biomarker for efficacy? As such, we need to improve clinical and molecular biomarkers to allow identification of early toxicity.

Next, Trop-2 is highly expressed across multiple types of cancer in the TCGA database, with high expression in urothelial carcinoma. The Trop-2 antibody drug conjugates include sacituzumab govitecan and datopotamab deruxtecan:

In the phase II TROPHY-U-01 trial³ that led to FDA accelerated approval for sacituzumab govitecan in pretreated locally advanced or metastatic urothelial carcinoma, toxicity was significant and led to treatment disruptions and dose reductions:

Datopotamab deruxtecan in TROPION-PanTumor01 included 33 patients with urothelial carcinoma, with relevant adverse events including grade 3 stomatitis (6%) and grade 3 diarrhea (3%). For oral mucositis/stomatitis, patients should gently brush their teeth, use a daily steroid mouthwash, and educate on the importance of oral hygiene. For ocular surfaces, patients should use artificial tears as needed, and avoid contact lenses.

For HER2, the antibody drug conjugates include trastuzumab deruxtecan and disitamab vedotin. In the DESTINY-PanTumor02 trial assessing trastuzumab deruxtecan,⁴ drug-related treatment emergent events of interest included nausea (any grade 54.3%), fatigue (any grade 37.8%), and neutropenia (any grade 32.8%). For trastuzumab deruxtecan related interstitial lung disease (15% after exposure to trastuzumab deruxtecan), the five “S” rules apply:

1. Screening: careful patient selection is warranted before initiating trastuzumab deruxtecan and screening continues during treatment, with regular clinical assessments
2. Scanning: A baseline CT-scan is recommended, with repeat scans to be performed every 6-12 weeks
3. Synergy: Minimizing the risk of interstitial lung disease involves teamwork
4. Suspending treatment: Trastuzumab deruxtecan should always be interrupted if interstitial lung disease is suspected
5. Steroids: The mainstay for treating trastuzumab deruxtecan-induced interstitial lung disease remains corticosteroids, with dose adapted to the toxicity grade

In 2024, Sheng and colleagues [5] assessed the efficacy and safety of disitamab vedotin in two phase II trials of patients with HER2-positive locally advanced or metastatic urothelial carcinoma. The most common treatment related adverse events were peripheral sensory neuropathy (68.2%), leukopenia (50.5%), AST increase (42.1%), and neutropenia (42.1%). Overall, 54.2% of patients experienced grade 3+ treatment related adverse events, including peripheral sensory neuropathy (18.7%), and neutropenia (12.1%).

Dr. Castellano concluded his presentation discussing overcoming the challenges of antibody drug conjugate toxicity in bladder cancer with the following take-home points:

• Antibody drug conjugates have improved the activity of traditional chemotherapy regimens and still confer frequent and sometimes life-threatening toxicities
• Given the rapid expansion in their indications, an awareness of these adverse events and their management is crucial to prevent and mitigate antibody drug conjugate-related toxicities, including clinical trials for early disease (VOLGA, EV 304, SURE-01)
• Important and potential practice change innovations in antibody drug conjugate design, biomarker development, and combination therapies are needed
• Patient stratification and biomarker identification will be relevant to maximize the clinical benefits of these emerging antibody drug conjugates, including academic and real world data programs 

Presented by: Daniel Castellano, MD, Servicio de Oncología Médica, Hospital Universitario 12 de Octubre, Madrid, Spain

Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2025 Genitourinary (GU) American Society of Clinical Oncology (ASCO) Annual Meeting, San Francisco, CA, Thurs, Feb 13 – Sat, Feb 15, 2025. 

References:

1. Powles T, Rosenberg JE, Sonpavde GP, et al. Enfortumab Vedotin in Previously Treated Advanced Urothelial Carcinoma. N Engl J Med 2021 Mar 25;384(12):1125-1135.
2. Powles T, Valderrama BP, Gupta S, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024 Mar 7;390(10)875-888.
3. Tagawa ST, Balar AV, Petrylak DP, et al. Metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors. J Clin Oncol. 2021 Aug 1;39(22):2474-2485.
4. Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: Primary results form the DESTINY-PanTumor02 Phase II Trial. J Clin Oncol. 2024 Jan 1;42(1):47-58.
5. Sheng X, Wang L, He W, et al. Efficacy and Safety of Disitamab Vedotin in Patients with Human Epidermal Growth Factor Receptor 2-Positive Locally Advanced or Metastatic Urothelial Carcinoma: A Combined Analysis of Two Phase II Clinical Trials. J Clin Oncol. 2024 Apr 20;42(12):1391-1402.