EV-103: Enfortumab Vedotin Plus Pembrolizumab in Urothelial Carcinoma


Dr. Tagawa offers his initial impressions on the second patient case and discusses data on enfortumab vedotin plus pembrolizumab for patients with urothelial carcinoma.

Case 2: A 76-Year Old Man with Locally Advanced, Resectable Urothelial Carcinoma

Initial Clinical Presentation: 

  • A 76-year-old man presented to the clinic with complaints of dizziness and hematuria.
  • PMH: hypercholesterolemia (well controlled with medication) and mild COPD.
  • SH: Patient does not smoke or drink alcohol.

Initial Clinical Workup: 

  • CT Imaging: Chest, abdomen, and pelvis revealed a 3.5-cm mass in the bladder and multiple liver metastases.
  • ECOG PS 1
  • eGFR > 60 mL/min (cisplatin-eligible kidney function)
  • Lung Biopsy confirmed stage IV urothelial carcinoma.
  • Molecular testing: FGFR2/3 mutation and fusion negative

Treatment and Disease Progression:

  • Patient is initiated with neoadjuvant gemcitabine plus cisplatin for 4 cycles.
    • He achieved a partial response following chemotherapy.
    • Following neoadjuvant therapy, the patient undergoes surgical resection of the tumor.
    • While discussed with his oncology care team, the patient did not receive maintenance treatment.
  • 6 months following surgery, patient demonstrates disease progression based after routine follow up and repeat imaging.
    • Patient progresses to muscle-invasive metastatic urothelial carcinoma.
    • Patient is started on combination pembrolizumab plus enfortumab vedotin-ejfv.
      • Pembrolizumab 200 mg IV every 3 weeks; enfortumab 1.25 mg/kg IV infusion over 30 minutes on Days 1 and 8 for every 21-day cycle.
      • 12 hours post-infusion, the patient developed a maculopapular rash and was improved with supportive care (topical hydrocortisone cream).
    • Achieves partial response after 6 cycles.
  • Following initial systemic therapy, patient is evaluated in a routine follow up visit and demonstrates further disease progression.
    • After discussion with his oncology care team, the patient is initiated on sacituzumab govitecan 10 mg/kg IV on D1 and D8 for 21-day cycles.
      • 48 hours following start of therapy, patient notices feeling dehydrated and having more frequent bowel movements. His oncologist starts him on oral loperamide to manage his diarrhea. Two days later, the patient’s diarrhea was resolved.

This is a synopsis of a Case-Based Peer Perspectives series featuring Scott T. Tagawa, MD, MS, FACP, FASCO, of Weill Cornell Medicine.

Scott T. Tagawa, MD, MS, FACP, FASCO summarized key learnings from the case presentations on evolving treatment approaches for metastatic urothelial carcinoma. A key factor is determining cisplatin eligibility, as options differ for cisplatin-fit versus cisplatin-ineligible patients.

For cisplatin-ineligible patients, he noted carboplatin-chemotherapy followed by maintenance pembrolizumab immunotherapy has been standard. However, in April 2023, the combination of enfortumab vedotin (antibody-drug conjugate targeting Nectin-4) plus pembrolizumab received accelerated FDA approval for the first-line setting based on results from cohort A and cohort K of the multi-arm phase 1/2 EV-103 study.

Cohort A showed high response rates and durable benefit with the combination. Cohort K randomized cisplatin-ineligible patients to enfortumab vedotin plus pembrolizumab versus enfortumab vedotin alone. This confirmed high response rates with the combination and demonstrated single agent activity for enfortumab vedotin.

Dr. Tagawa noted a press release revealed the combination beat platinum-based chemotherapy for advanced urothelial carcinoma in a phase 3 trial, making it the first regimen to improve on chemotherapy. More mature data are expected at ESMO 2023. Meanwhile, immunotherapy also improved outcomes when added to cisplatin-based chemotherapy per a press release.

In conclusion, treatment paradigms are rapidly shifting in metastatic urothelial carcinoma with new immunotherapies and antibody-drug conjugates. Biomarker analysis to select patients for targeted therapies remains important. Ongoing trials are aiming to optimize combinations and sequences to continue extending survival.

*Video synopsis is AI-generated and reviewed by Urology Times editorial staff.

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