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ESMO Open
ESMO Open
ESMO Open
2059-7029
Elsevier

S2059-7029(24)01495-9
10.1016/j.esmoop.2024.103725
103725
Correspondence
The clinical use of enfortumab vedotin and pembrolizumab in patients with advanced urothelial carcinoma: using clinical judgement over treatment criteria
Apolo A.B. 1
Bellmunt J. 2
Cordes L. 1
Gupta S. 3
Powles T. thomas.powles1@nhs.net
4
Rosenberg J.E. 5
Van Der Heijden M.S. 6
1 Center for Cancer Research, National Cancer Institute, Bethesda
2 Dana Farber Cancer Institute, Boston
3 Cleveland Clinic Taussig Cancer Institute, Cleveland, USA
4 Barts Cancer Centre, London, UK
5 Memorial Sloan Kettering, New York, USA
6 National Cancer Institute (NKI), Amsterdam, the Netherlands
05 9 2024
9 2024
05 9 2024
9 9 103725© 2024 Published by Elsevier Ltd on behalf of European Society for Medical Oncology.
2024

https://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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pmcEnfortumab vedotin and pembrolizumab (EVP) is the new standard of care in first-line advanced urothelial cancer.1, 2, 3 The combination is associated with significantly improved overall response rate, progression-free survival and overall survival, compared with platinum-based chemotherapy reported in the EV-302 phase 3 study, and it has a distinct toxicity profile characterized by skin rash and neuropathy. It is widely included in guidelines without specific restrictions based on baseline clinical parameters.2,3 As it becomes broadly integrated into clinical practice, there is a need for clarity on which patients are best suited for EVP, and in whom it should be avoided based on toxicity risk. Patients with poor performance status or active or serious medical conditions were largely excluded from clinical trials with EV and EVP, as pharmacokinetic data and safety were primarily evaluated in these studies, and these groups may have influenced the safety results. As we consider a real-world cohort, however, broader subgroups of patients may benefit from therapy with EVP after weighing risks and benefits.

The urothelial carcinoma community has a track record in generating criteria, such as the Galsky criteria for cisplatin use, to guide clinicians in order to avoid excess treatment-related toxicity and ensure appropriate therapy.4 With cisplatin, the toxicity and risk in patients with certain pre-existing conditions are clear; this is less so with EVP. Therefore, it is reasonable to ask whether a similar set of criteria are necessary for this new regimen. No such criteria exist for single agent EV or pembrolizumab therapy, both of which are widely used in urothelial carcinoma.5,6 Therefore, why now?

Consensus definitions and treatment criteria outside the setting of a clinical trial must be based on a clear and established relationship between drug and potential harm to justify the approach. With the exception of the Galsky criteria, the generation of this type of guidance is uncommon in cancer treatment. For example, there are limited treatment criteria based on baseline comorbidities for vascular endothelial growth factor (VEGF)-targeted therapy or programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] inhibition. Instead, clinicians assess the risk–benefit ratio associated with the treatment in the context of their underlying knowledge of comorbidities. There may be a need to address medical conditions before starting therapy, such as hypertension for VEGF inhibitors,7 but excluding patients with well-controlled pre-existing conditions would unnecessarily limit access to effective treatments. A balanced strategy to allow EVP to be safely accessible includes using clinical judgement regarding baseline comorbidities, close monitoring while on treatment, and dose interruption considerations for select toxicities.

The EV (PADCEV) package insert, available free online, provides practitioners a comprehensive list of common adverse events with a dose modification table, and an outline of warnings and precautions based on clinical trial data.8 Special precautions include skin reactions, hyperglycemia, pneumonitis, peripheral neuropathy, and ocular disorders. There are important considerations before administering EV in patients with pre-existing conditions. For example, uncontrolled diabetes would need to be addressed before starting treatment. While EV is associated with hyperglycemia and rarely ketoacidosis (in patients with or without diabetes mellitus), select patients with a history of diabetes mellitus may derive benefit from EV with close glucose monitoring in consultation with an endocrinologist. Rather than delaying the start of EV in patients with an elevated hemoglobin A1c, it may be advantageous to implement an EV dose interruption approach for a blood glucose of >250 mg/dl. Ocular disorders, primarily dry eye, have been reported with EV. Since no evidence suggests that patients with baseline corneal or retinal abnormalities are at increased risk of severe events, treatment should be at the discretion of the oncologist in conjunction with a patient’s ophthalmologist. Low creatine clearance has been suggested as a relative contraindication for EVP, despite a lack of evidence that this predisposes to toxicity.9,10 Pharmacokinetic studies of EV demonstrated no clinically significant differences in patients with severe renal impairment.11 Similarly, pembrolizumab may be used in patients with altered kidney function without dose adjustment.12 Therefore, renal function should not be a major barrier to the use of EVP. Overlapping toxicities of EV and pembrolizumab include skin reactions. For EV-associated skin reactions, there is a lack of evidence that pre-existing skin conditions, such as psoriasis, predispose to EV-related skin toxicities. While certain skin disorders may be considered a relative contraindication to pembrolizumab, there has been no need in the past to set baseline treatment criteria and the oncology community’s comfort in using immune checkpoint inhibitors has evolved with experience.

This leads to the question around why we would need potentially restrictive criteria for EVP which may unnecessarily remove patients from consideration for this active treatment. Whereas life-threatening toxicity in a minority of patients is a real issue requiring proper training for early recognition, the evidence that pre-existing conditions can lead to a higher risk of EV-associated severe toxicity currently does not exist. Incorporating knowledge around the relative and absolute contraindications (e.g. high-grade peripheral neuropathy, moderate/severe hepatic impairment, active systemic infection) in the overall education of prescribers, in addition to sharing clinical experience, are more useful than fixed criteria based on loosely related conditions, which can potentially be addressed. Focusing on education around this new combination to familiarize practitioners with the unique toxicities will increase the comfort in the use of EVP. The expanded clinical use of EVP, an effective systemic therapy that prolongs overall survival in patients with advanced urothelial carcinoma, will lead to evolving expertise in how to rationally assess the risk/benefit balance in patients with pre-existing conditions.

Funding

None declared.

Disclosure

TP reports receiving grants, honoraria and consulting fees from AstraZeneca, Bristol Myers Squibb (BMS), Exelixis, Incyte, Ipsen, MSD, Novartis, Pfizer, Seattle Genetics, Merck Serono (EMD), Astellas, Johnson & Johnson, Eisai, Roche, Mashup. JR reports receiving funding from Astellas, Seagen, Merck, BMS, AstraZeneca, Gilead, EMD Serono, Lilly Oncology, Aktis, Aadi Bioscience; Alligator Bioscience; Bayer; Boehringer Ingelheim; Century Therapeutics; Hengrui; Imvax; Tyra Biosciences, Roche/Genentech, AstraZeneca, Seagen/Pfizer, Astellas, Acrivon, Lilly Oncology, EMD-Serono, Pfizer; RTP, Medscape, MJH Life Sciences, Clinical Care Options, Mashup Media, Clinical Education Alliance; Wolters Kluwer Health; PSL. MSVDH reports receiving research funding from BMS, Merck/MSD, AstraZeneca, Roche and 4SC (all paid to institute) and consulting fees from BMS, Merck/MSD, AstraZeneca, Astellas, Pfizer, Seagen, and Janssen (all paid to institute). SG reports the following conflicts: Seattle Genetics, Pfizer, EMD Serono, Merck, Gilead Sciences, BMS, Novartis, Bayer, Signetara, Astellas, Genzyme, Nektar Therapeutics, BioNTech. JB reports financial interests in Pfizer, AstraZeneca, Merck, BMS, MSD, Bicycle, UpToDate, and non-financial interests in Genentech and ASCO. All other authors have declared no conflicts of interest.
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