(UroToday.com) The 2023 ESMO annual meeting included a session on novel targets, therapies and toxicities in genitourinary cancers, featuring a presentation by Dr. Yohann Loriot discussing new toxicities for antibody-drug conjugates and FGFR-directed therapies. Dr. Loriot started by highlighting that there are several new classes of drugs approved or being investigated in genitourinary oncology:
Discussing antibody drug conjugates, Dr. Loriot highlighted that these agents are particularly effective in urothelial carcinoma. By targeting NECTIN-4, TROP-2 and HER2, there is high effectiveness for intratumoral drug concentration and efficient cancer cell killing, lowering systemic distribution and off-target effects:
Antibody drug conjugates have an interplay between delivering a cytotoxic payload and antitumor effects of the antibody (ie. inhibition of oncogenic signaling pathways, enhancement of antitumor immunity through the induction of ADCC), with this complex combination of these two treatment modalities leading to both efficacy and toxicity. Dr. Loriot offers the following explanation for the mechanism of action and the potential impact on toxicity:
Specific antibody related toxicities include the following based on their intended target:
- NECTIN-4: rash and mucositis
- HER2: cardiotoxicity
- TROP2: diarrhea and mucositis
The following highlights several of the enfortumab vedotin skin toxicities:
Factors associated with antibody drug conjugate-related toxicity are summarized by the payload and the linker:
- Payload: premature deconjugation of the lipophilic payload, binding to albumin and increased half-life, non-specific endocytosis of the intact antibody-drug conjugate with non-malignant cells, and interaction of the Fc domain of the antibody-drug conjugate with Fc receptors of IC
- Linker: (i) for cleavable, early release of the free payload into circulation; (ii) for non-cleavable, prolonged circulation of the intact antibody-drug conjugate and late release in variable locations (ie. the eyes)
There are also several unusual pharmacokinetic factors associated with antibody-drug conjugate-related toxicities, including renal and liver dysfunction, polymorphism in genes (UGT1A1 and SG), body composition (sarcopenia), and ethnicity (ie. Asian population).
Taken together, there are several solutions to mitigate antibody drug conjugate-associated toxicities: dosing-based solutions, biotechnology solutions, pharmacogenomics solutions, and clinical-based solutions. Dosing-based solutions are highlighted in the subsequent figure:
Technology-based solutions include bispecific antibody drug conjugates, masking the binding domains with pro-antibody drug conjugates, and Fc domain silencing:
Additionally, technology may assist with improving antibody drug conjugate stability in circulation, new payloads, and combining two different payloads to the same antibody drug conjugate. Pharmacogenomics solutions include identification of patients with the greatest risk of developing adverse events and monitoring these patients more closely. Polymorphisms affecting genes that encode enzymes involved in payload metabolism and those involved in payload release or in those encoding Fc receptors may be important. Potential clinical solutions are highlighted as follows:
Dr. Loriot then discussed toxicities of FGFR inhibitors, highlighting that non-selective FGFR inhibitors have off target toxicities and selective FGFR inhibitors have class-effect toxicities. Common toxicities include ophthalmic, hepatic, GI, skin, and laboratory abnormalities:
For skin toxicities (onycholysis and paronychia), toxicity related to nails has a median onset of 69 days and median time to resolution of > 75 days. For hand-foot syndrome, the median time to onset is 42 days and the median time to resolution is > 90 days. Central serous retinopathy is mostly reversible and has a median time to resolution of ~4 weeks. These patients need a baseline OCT and frequent monitoring. Solutions to mitigate FGFR inhibitor toxicities include:
- Response based dose adjustments
- Development of selective FGFR3 inhibitors
- Development of new technology to avoid toxicity in the early stage
Dr. Loriot concluded his presentation discussing new toxicities for antibody drug conjugates and FGFR-directed therapies with the following take-home points:
- New drugs with new mechanisms of action mean new toxicities
- Education of patients and the whole team (ie. nurses, fellows, etc) is key
- There is a learning curve to managing these toxicities
- Several strategies to reduce the toxicity will be tested and implemented
- Antibody drug conjugates and targeted therapies are really good drugs
Presented by: Yohann Loriot, MD, PhD, Gustave Roussy, Université Paris-Saclay, Villejuif, Cedex, France
Written by: Zachary Klaassen, MD, MSc – Urologic Oncologist, Associate Professor of Urology, Georgia Cancer Center, Wellstar MCG Health, @zklaassen_md on Twitter during the 2023 European Society of Medical Oncology (ESMO) Annual Meeting, Madrid, Spain, Fri, Oct 20 – Tues, Oct 24, 2023.