Managing potential adverse events during treatment with enfortumab vedotin + pembrolizumab in patients with advanced urothelial cancer

Abstract

Cisplatin-based chemotherapy has been the standard of care for patients with locally advanced or metastatic urothelial cancer (la/mUC). Enfortumab vedotin, an antibody-drug conjugate directed to Nectin-4, and pembrolizumab, an immune checkpoint inhibitor, are two therapies that have individually provided a survival benefit in patients with la/mUC. The combination regimen of enfortumab vedotin plus pembrolizumab was evaluated in EV-302 (KEYNOTE-A39; NCT0422385), a phase 3 study that showed statistically significant and clinically meaningful improvement in overall survival, progression-free survival, and a key secondary endpoint of overall response rate versus chemotherapy. Based on these results and those from the EV-103 (KEYNOTE-869; NCT03288545) Dose Escalation cohort, Cohort A, and Cohort K, enfortumab vedotin plus pembrolizumab was granted approval from the US Food and Drug Administration for the treatment of adults with la/mUC. While guidelines and recommendations for the management of adverse events (AEs) have been developed for immune checkpoint inhibitor monotherapy and enfortumab vedotin monotherapy, additional guidance is needed for managing AEs that occur with enfortumab vedotin plus pembrolizumab. As monotherapies, enfortumab vedotin and pembrolizumab are both associated with some of the AEs observed with the combination, such as skin reactions, pneumonitis, and diarrhea, which may confound the attribution of the AE to a specific agent and thereby complicate clinical management. In this manuscript, we aim to provide recommendations for best practice for patient care and the management of AEs of clinical interest for patients with la/mUC receiving enfortumab vedotin plus pembrolizumab, including skin reactions, peripheral neuropathy, hyperglycemia, and pneumonitis. These recommendations were developed based on published guidelines, expert opinions, and the clinical experience of the authors, which include oncologist, advanced practice provider, nursing, and pharmacy perspectives. In addition, guidance on patient education and communication is provided. With vigilant monitoring, early detection, and prompt intervention of treatment-emergent AEs based on recommended approaches described herein, it is the authors' experience that most AEs can be managed with supportive therapy and dose modification/interruptions, allowing patients to continue treatment.

Keywords: adverse events; anticancer therapy; enfortumab vedotin; immune-related adverse events; irAE; pembrolizumab; urothelial cancer.

Figure 1

Median times to onset of select AEs in patients with la/mUC treated with EV + Pembro (N = 564). An AE may occur at any timepoint. Data reflect patients with urothelial cancer who received at least one dose of EV + Pembro from EV-302 and EV-103 (N = 564). Treatment consisted of EV 1.25 mg/kg (on days 1 and 8 of a 21-day cycle) and Pembro 200 mg (on day 1 of a 21-day cycle). Grading based on NCI CTCAE Version 4.03 ( Supplementary Table 2 ) (35). AE, adverse event; EV, enfortumab vedotin; EV + Pembro, enfortumab vedotin plus pembrolizumab combination; la/mUC, locally advanced or metastatic urothelial cancer; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; Pembro, pembrolizumab. ^*Time to first onset for Dose Escalation Cohort/Cohort A (N = 45). Median onset for Cohort K was 0.53 months (N = 76) (26). ^†Skin reactions of any grade may occur as early as the first cycle. ^‡The EV US prescribing information uses the term “pneumonitis/interstitial lung disease” (22).

Figure 2

Risk factors and recommendations for the prevention, monitoring, and management of treatment-emergent skin reactions. Grading based on NCI CTCAE Version 4.03 ( Supplementary Table 2 ) (35). EV, enfortumab vedotin; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; OTC, over the counter; Pembro, pembrolizumab; SJS, Stevens–Johnson syndrome; TEN, toxic epidermal necrolysis. ^†Recommendations based on clinical experience.

Figure 3

Risk factors and recommendations for the prevention, monitoring, and management of treatment-emergent peripheral neuropathy. Grading based on NCI CTCAE Version 4.03 ( Supplementary Table 2 ) (35). ADC, antibody-drug conjugate; AE, adverse event; EV, enfortumab vedotin; MMAE, monomethyl auristatin E; mUC, metastatic urothelial cancer; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; Pembro, pembrolizumab. ^†Recommendations based on clinical experience.

Figure 4

Risk factors and recommendations for the prevention, monitoring, and management of treatment-emergent hyperglycemia. Grading based on NCI CTCAE Version 4.03 ( Supplementary Table 2 ) (35). BMI, body mass index; DKA, diabetic ketoacidosis; DM, diabetes mellitus; EV, enfortumab vedotin; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; Pembro, pembrolizumab; T1DM, type 1 diabetes mellitus. ^†Recommendations based on clinical experience.

Figure 5

Risk factors and recommendations for the prevention, monitoring, and management of treatment-emergent pneumonitis^*. Grading based on NCI CTCAE Version 4.03 ( Supplementary Table 2 ) (35). EV, enfortumab vedotin; ICU, intensive care unit; NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; Pembro, pembrolizumab. ^*The EV US prescribing information uses the term “pneumonitis/interstitial lung disease” (22). ^†Recommendations based on clinical experience.