Jens Bedke, MD, is a senior consultant in the Department of Urology & Transplantation Surgery at the Eva Mayr-Stihl Cancer Center Stuttgart, Klinikum Stuttgart in Germany.

Bedke

“The efficacy [data], which are so strong and have such an enormous delta [in favor of] enfortumab vedotin plus pembrolizumab in this first-line setting, justify the use, more or less, in all patients.”

Jens Bedke, MD, a member of the Department of Urology at the Eva Mayr-Stihl Cancer Center in German, and a professor of urology at the University of Tübingen, discussed practical considerations for incorporating enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) into the frontline treatment paradigm for patients with previously untreated advanced urothelial carcinoma. 

Data from the phase 3 EV-302 trial (NCT04223856) demonstrated that enfortumab vedotin plus pembrolizumab significantly improved progression-free survival, overall survival, and objective response rates compared with platinum-based chemotherapy, establishing the combination as the preferred standard of care for eligible patients. According to Bedke, the benefit of enfortumab vedotin plus pembrolizumab was consistent across all evaluated subgroups, regardless of metastatic site or primary tumor location, including lymph node, liver, upper tract, and lower tract. Therefore, disease distribution should not guide patient selection for enfortumab vedotin plus pembrolizumab, he said. Instead, enfortumab vedotin plus pembrolizumab should be considered broadly in the first-line setting given its efficacy advantage over platinum regimens, he explained. Bedke noted that many oncologists are already familiar with both agents individually: pembrolizumab from its use as a checkpoint inhibitor and enfortumab vedotin from its approved role as monotherapy in later-line settings. The combination leverages this prior experience but requires awareness of overlapping and unique toxicities.

Key adverse effects associated with enfortumab vedotin plus pembrolizumab that oncologists should be aware of include dermatologic reactions, peripheral neuropathy with both sensory and motor components, hyperglycemia, and ocular toxicities, he stated. Although enfortumab vedotin plus pembrolizumab is appropriate for most patients with advanced urothelial carcinoma, Bedke advised caution in select populations. Contraindications include prior organ transplantation and severe immune-related disorders that preclude the safe administration of checkpoint inhibitors, he added. Outside of these scenarios, enfortumab vedotin plus pembrolizumab is endorsed by international guidelines as a preferred first-line regimen, he concluded.

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Jens Bedke, MD, discusses considerations for using enfortumab vedotin plus pembrolizumab in the frontline setting for advanced urothelial carcinoma.

Dr Bedke on Advice for Using Enfortumab Vedotin/Pembrolizumab in Previously Untreated Advanced Urothelial Carcinoma

“We must be careful in managing these patients and be aware of the specific [adverse] effect profile. It’s not that a specific subgroup [was more or less prevalent] than the other, and this is a good signal for the clinical setting.”

Jens Bedke, MD, a senior consultant in the Department of Urology and Transplantation at the Eva Mayr-Stihl Cancer Center, discussed the safety profile of enfortumab vedotin (Padcev) plus pembrolizumab (Keytruda) compared with platinum-based chemotherapy in patients with previously untreated locally advanced or metastatic urothelial carcinoma. He emphasized that, in the intent-to-treat population, the incidence of grade 3 or 4 adverse effects [AEs] was numerically similar between the 2 treatment groups. However, the toxicity profile differed meaningfully, with the enfortumab vedotin–pembrolizumab regimen associated with distinct adverse effects of special clinical interest compared with chemotherapy.

Platinum-based chemotherapy was primarily associated with hematologic toxicities, which were notably absent with enfortumab vedotin/pembrolizumab, Bedke continued. Instead, patients receiving enfortumab vedotin/pembrolizumab experienced dermatologic toxicities, including rash and other skin disorders, as well as sensory and motor polyneuropathy, he explained. Additionally, ocular AEs such as blurred vision and other eye disorders were observed, with cases spanning multiple subcategories, he said.

Bedke noted that these treatment-related AEs require recognition and proactive management in the clinical setting. The distinct safety profile of enfortumab vedotin/pembrolizumab underscores the need for early detection and intervention for skin, neurologic, and ocular toxicities, which could differ in both onset and clinical management from the hematologic events typically seen with chemotherapy, he added.

Importantly, subgroup analyses showed no significant differences in the type or frequency of these AEs across clinical subgroups, including patients with liver metastases compared with those with only lymph node–only disease, Bedke asserted. This suggests that the safety profile of enfortumab vedotin/pembrolizumab is consistent regardless of disease burden or metastatic pattern, offering reassurance for its applicability across a broad range of patient presentations, he explained.

Bedke stressed that although the overall severity of AEs is comparable to chemotherapy, clinicians should anticipate and monitor for the unique toxicities associated with enfortumab vedotin/pembrolizumab. 

Jens Bedke, MD, discusses the safety of enfortumab vedotin and pembrolizumab in previously untreated locally advanced or metastatic urothelial carcinoma.

Dr Bedke on the Safety Profile of Enfortumab Vedotin/Pembrolizumab in Previously Untreated Advanced Urothelial Carcinoma

Dr Bedke on Enfortumab Vedotin Plus Pembrolizumab in Urothelial Carcinoma

“There was a pronounced benefit with enfortumab vedotin plus pembrolizumab compared with platinum-based chemotherapy [in patients with previously untreated urothelial cancer]. There was no specific subgroup [for whom] you should decide not to use enfortumab vedotin plus pembrolizumab.”

Jens Bedke, MD, a senior consultant in the Department of Urology & Transplantation Surgery at the Eva Mayr-Stihl Cancer Center Stuttgart, Klinikum Stuttgart, discussed findings from subgroup analyses of the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856), which evaluated enfortumab vedotin (Padcev) plus pembrolizumab (Keytruda) vs chemotherapy alone in patients with untreated locally advanced or metastatic urothelial cancer.

 showed that enfortumab vedotin plus pembrolizumab generated superior progression-free survival (PFS), overall survival (OS), and overall response rates (ORR) compared with chemotherapy across all prespecified subgroups of interest, Bedke began. Subgroups included patients with upper tract and lower tract disease, lymph node–only metastases, visceral metastases, and liver metastases, he continued. Therefore, enfortumab vedotin plus pembrolizumab should be considered regardless of patient subgroup classification, he asserted.

The median PFS among patients with primary disease in the upper tract in the investigational (n = 135) and chemotherapy (104) arms was 12.3 months (95% CI, 7.6-16.4) and 6.2 months (95% CI, 6.1-6.9), respectively (HR, 0.542; 95% CI, 0.384-0.763). Patients with visceral metastases in the investigational (n = 318) and control (n = 318) arms achieved a median PFS of 10.4 months (95% CI, 8.3-12.7) and 6.2 months (95% CI, 6.0-6.3), respectively (HR, 0.477; 95% CI, 0.393-0.579).

The respective median PFS values among those with lymph node–only metastases in the investigational (n = 103) and control (n = 104) arms were 22.1 months (95% CI, 15.3-not evaluable) and 8.3 months (95% CI, 6.2-13.1; HR, 0.473; 95% CI, 0.317-0.704). Patients with liver metastases in the investigational (n = 100) and control (n = 99) arms had a median PFS of 8.1 months (95% CI, 6.1-12.0) and 6.0 months (95% CI, 4.4-6.3), respectively (HR, 0.548; 95% CI, 0.392-0.766).

Bedke noted that the benefit achieved with the enfortumab vedotin combination was particularly notable in patients with lymph node–only metastases. These patients achieved a complete response rate of 50% and an ORR of 77.5% with enfortumab vedotin plus pembrolizumab, he concluded.

Jens Bedke, MD, discusses findings from subgroup analyses of the phase 3 EV-302/KEYNOTE-A39 trial in untreated metastatic urothelial cancer.

Jens Bedke, MD

Articles

Dr Bedke on Advice for Using Enfortumab Vedotin/Pembrolizumab in Previously Untreated Advanced Urothelial Carcinoma

Dr Bedke on the Safety Profile of Enfortumab Vedotin/Pembrolizumab in Previously Untreated Advanced Urothelial Carcinoma

Dr Bedke on Enfortumab Vedotin Plus Pembrolizumab in Urothelial Carcinoma