Dr Lee on the Efficacy of Enfortumab Vedotin Plus Pembrolizumab in Urothelial Cancer

“Probably the most important [bladder cancer treatment update] is the approval of enfortumab vedotin plus pembrolizumab as frontline therapy for locally advanced and metastatic urothelial carcinoma.”

John K. Lee, MD, PhD, associate professor-in-residence, Division of Hematology/Oncology, Department of Medicine; the Institute for Urologic Oncology, Department of Urology, the David Geffen School of Medicine, UCLA Heath, discusses the significance of the phase 3 EV-302 trial (NCT04223856) investigating enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) in the first-line setting in patients with locally advanced or metastatic urothelial cancer.

One of the most important recent advancements in bladder cancer management has been the 2023 

FDA approval of enfortumab vedotin plus pembrolizumab

 as frontline therapy for patients with locally advanced or metastatic urothelial carcinoma, Lee begins. For decades, the standard first-line treatment for this patient population was platinum-based chemotherapy, which long remained the cornerstone of therapy despite limited success in improving disease outcomes, Lee describes.

The pivotal EV-302 trial combined the antibody-drug conjugate enfortumab vedotin with the immune checkpoint inhibitor pembrolizumab and compared this regimen with standard chemotherapy. Enfortumab vedotin plus pembrolizumab generated substantial improvements in overall survival (OS) and progression-free survival (PFS), Lee notes. The median PFS was 12.5 months (95% CI, 10.4-16.6) with the combination (n = 442) vs 6.3 months (95% CI, 6.2-6.5) with chemotherapy (n = 444; HR, 0.45; 95% CI, 0.38-0.54; 

 < .001). The median OS in these respective arms was 31.5 months (95% CI, 25.4-not reached [NR]) and 16.1 months (95% CI, 13.9-18.3 [HR, 0.47; 95% CI, 0.38-0.58; 

Furthermore, the overall response rate with the combination was 67.7% (95% CI, 63.1%-72.1%) vs 44.4% (95% CI, 39.7%-49.2%) with chemotherapy. Complete responses were observed in 29.1% and 12.5% of patients in the combination (n = 437) and chemotherapy arms (n = 441), respectively. The median duration of response was NR (95% CI, 20.2 months-NR) with enfortumab vedotin plus pembrolizumab vs 7.0 months (95% CI, 6.2-10.2) with chemotherapy. These findings have established enfortumab vedotin plus pembrolizumab as a superior therapeutic option over chemotherapy in patients with advanced or metastatic urothelial cancer, irrespective of cisplatin eligibility, Lee concludes.

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John K. Lee, MD, PhD, discusses the EV-302 trial of frontline enfortumab vedotin plus pembrolizumab in locally advanced or metastatic urothelial cancer.

Dr Lee on the Significance of the Tumor-Agnostic Approval of T-DXd for HER2+ Urothelial Cancer

John K. Lee, MD, PhD, assistant professor, medicine, UCSF; director, Bladder Cancer Program, UCSF Helen Diller Family Comprehensive Cancer Center, discusses the significance of the tumor-agnostic approval of fam-trastuzumab deruextecan-nxki (Enhertu; T-DXd) in patients with HER2-positive urothelial cancer.

The FDA granted accelerated approval to T-DXd

 for the treatment of adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors who have received prior systemic therapy and have no satisfactory alternative treatment options in April, 2024, Lee begins. The regulatory decision was supported by data from the phase 2 DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831) trials, he reports. Across all studies, T-DXd was shown to have significant efficacy across a range of HER2-positive solid tumors, Lee says.

The DESTINY-PanTumor02 study evaluated the efficacy of T-DXd at a dose of 5.4 mg/kg every 3 weeks in patients with locally advanced or metastatic HER2-positive disease who had undergone at least one prior line of systemic therapy, Lee continues. This trial enrolled eligable patients across 7 different cohorts based on tumor type, comprising endometrial, cervical, ovarian, bladder, biliary tract, and pancreatic cancers, as well as other advanced solid tumors, he details.

The trial's findings revealed that patients with HER2-positive IHC 3+ tumors achieved notably higher response rates compared with those with HER2-positive IHC 2+ tumors, Lee reports. Importantly, T-DXd demonstrated significant progression-free survival benefits for patients in the IHC 3+ group, further solidifying its role as a promising therapeutic option. These results were consistent across multiple tumor types, establishing T-DXd as an effective treatment in a tumor-agnostic fashion for patients with HER2-positive cancers, Lee says. This approval is not only significant for patients with bladder cancer, but is impactful across the board for patients who have no other available treatment options, he concludes.

John K. Lee, MD, PhD, discusses the significance of the tumor-agnostic approval of T-DXd specifically for patients with HER2-positive urothelial cancer.

Dr Lee on Safety Considerations for Enfortumab Vedotin in Metastatic Urothelial Cancer

John K. Lee, MD, PhD, assistant professor, medicine, University of California, San Francisco (UCSF); director, Bladder Cancer Program, UCSF Helen Diller Family Comprehensive Cancer Center, discusses safety considerations for enfortumab vedotin-ejfv (Padcev), an antibody-drug conjugate (ADC) in the treatment of metastatic urothelial cancer.

Enfortumab vedotin targets NECTIN-4, a protein expressed in tumor cells that is also expressed in normal tissues, including the gastrointestinal (GI) tract, esophagus, and skin, which contributes to its unique adverse effect (AE) profile.

Lee explains that one of the most concerning AEs associated with enfortumab vedotin is the risk of severe skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. These toxicities require prompt identification and management, as they can be life-threatening if not addressed early, he says, noting that dermatologic monitoring is crucial throughout the treatment course to mitigate potential severe skin toxicities.

NECTIN-4 expression in the GI tract can also lead to AEs such as diarrhea, nausea, and mucositis, Lee continues. These symptoms can significantly impact a patient's quality of life and may require supportive care measures, including antiemetics and hydration.

Peripheral neuropathy is a common and progressive toxicity associated with enfortumab vedotin, often related to its chemotherapeutic component. The development of neuropathy can be debilitating and affect patients' daily activities and overall quality of life, Lee explains. Vigilance in monitoring for early signs of neuropathy is essential, and dose modifications or discontinuation may be required based on the severity of symptoms.

Since enfortumab vedotin is approved in the frontline setting in combination with pembrolizumab (Keytruda), the use of the antibody-drug conjugate with an immune checkpoint inhibitor adds another layer of safety considerations. Immune-related AEs (irAEs), which can range from mild to severe, are also something to monitor with this combination, Lee says. These irAEs also necessitate close monitoring and a proactive management approach, including the use of corticosteroids or other immunosuppressive agents when appropriate.

Lee concludes that the safety profile of enfortumab vedotin necessitates careful monitoring for these specific AEs to optimize patient outcomes and minimize treatment-related toxicities.

John K. Lee, MD, PhD, discusses safety considerations for enfortumab vedotin in the treatment of metastatic urothelial cancer. 

Dr Lee on Treatment Considerations for Enfortumab Vedotin Plus Pembrolizumab in Urothelial Cancer

John K. Lee, MD, PhD, assistant professor, medicine, University of California, San Francisco; director, Bladder Cancer Program, UCSF Helen Diller Family Comprehensive Cancer Center, discusses key considerations that may inform the use of enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) in metastatic urothelial cancer.

On December 15, 2023, the FDA approved enfortumab vedotin in combination with pembrolizumab as frontline therapy for patients with metastatic urothelial cancer. The regulatory decision was based on results from the phase 3 EV-302 trial (NCT04223856), which demonstrated a survival benefit with the combination compared with standard chemotherapy.

Lee begins by emphasizing the importance of individualized treatment decisions for patients with metastatic urothelial cancer, as well as factoring in potential treatment-related toxicities. Although the combination of enfortumab vedotin and pembrolizumab has shown superior clinical efficacy, it also presents specific challenges, he notes. For example, the higher risk of developing hyperglycemia, especially in patients with uncontrolled diabetes, highlights the need for careful patient selection when considering the selection of this combination.

Notably, the median follow-up for EV-302 was approximately 17.2 months, which generates questions about the long-term durability of the combination, Lee explains. This is a key consideration when juxtaposed with the well-established efficacy of cisplatin-based chemotherapy plus immunotherapy, which support its use in patients with lymph node-only disease.

Moreover, the immune checkpoint inhibitor pembrolizumab may not be suitable for patients with a history of solid organ transplants or autoimmune disorders, Lee adds. For these patients, upfront cisplatin-based chemotherapy alone may be a safer and more appropriate choice, he suggests.

Although the combination of enfortumab vedotin plus pembrolizumab offers a highly effective new treatment option for patients with metastatic bladder cancer, it is essential to tailor therapy based on individual patient characteristics, comorbidities, and potential contraindications to immunotherapy, Lee concludes.

John K. Lee, MD, PhD, discusses treatment considerations for the use of enfortumab vedotin plus pembrolizumab in metastatic urothelial cancer.

John K. Lee, MD, PhD

Articles

Dr Lee on the Efficacy of Enfortumab Vedotin Plus Pembrolizumab in Urothelial Cancer

Dr Lee on the Significance of the Tumor-Agnostic Approval of T-DXd for HER2+ Urothelial Cancer

Dr Lee on Safety Considerations for Enfortumab Vedotin in Metastatic Urothelial Cancer

Dr Lee on Treatment Considerations for Enfortumab Vedotin Plus Pembrolizumab in Urothelial Cancer