2. UroToday Home
  3. Clinical Trials
  4. From the Editor
Back to From the Editor Articles    

Improving upon Enfortumab Vedotin plus Pembrolizumab for First-Line Metastatic and Locally-Advanced Urothelial Carcinoma

For decades, platinum-based chemotherapy was the mainstay of first-line treatment, offering modest efficacy. Anticipated median survival was limited at around 15 months.1 Additionally, many patients are ineligible for cisplatin due to age, comorbidities, or poor performance status. Recent advances have transformed the treatment paradigm, particularly with the emergence of enfortumab vedotin (EV), in combination with pembrolizumab (pembro), as a highly efficacious first-line treatment option.

The EV-302/KEYNOTE-A39 trial was a pivotal Phase III, randomized, open-label study comparing EV plus pembro to standard platinum-based chemotherapy (cisplatin or carboplatin plus gemcitabine) in untreated locally advanced or metastatic urothelial carcinoma patients.2 This landmark trial included both cisplatin-eligible and ineligible patients. Median overall survival was 31.5 months (EV + Pembro) vs 16.1 months (chemo), HR 0.47, p<0.00001. Median progression-free survival was 12.5 months vs 6.3 months, HR 0.45, respectively. Objective response rate was also in favor of EV + Pembro over chemo, 68% vs 44%, with CRs in 29% vs 12%, respectively. These outcomes represent a near doubling of overall survival, with clearly the longest survival ever reported in the first-line setting of metastatic urothelial carcinoma. This supported the FDA approval of EV + Pembro.

Despite its potent efficacy, the combination has a manageable safety profile.2,3 Treatment discontinuation due to toxicity occurred in ~16% of patients, which is comparable to platinum-based chemotherapy. The most common and impactful adverse events are peripheral neuropathy (~60% all grades, ~6-10% grade ≥3) and skin rash (~60% all grades, ~7–10% grade ≥3). Other key reported adverse events are fatigue, alopecia, diarrhea, and hyperglycemia. Immune-related adverse events due to pembro (e.g., hypothyroidism, pneumonitis) occurred in a minority and were mostly manageable.

The impact of this new first-line regimen, with superior overall survival, progression-free survival, and objective response rate outcomes, is obvious. Couple that with the elimination of the need for chemotherapy in most patients, particularly those ineligible for cisplatin, and this represents a massive step forward in this field. This allows the expansion of effective treatment options to elderly, frail, and/or comorbid patients.

While the EV plus Pembro combination has become a new standard, several questions remain, and these warrant further investigation. I’ve outlined some thoughts below on areas that require study:

  • Duration of therapy: Optimal timing for treatment discontinuation or maintenance is unclear and should be thoroughly investigated, given clear potential for lasting side effects from EV, such as peripheral neuropathy.
  • Biomarkers of response: As PD-L1 expression does not clearly predict response to Pembro, exploration of Nectin-4 amplification and expression is providing some early hints for EV as a biomarker of outcome.4
  • Triplet strategies: Trials are evaluating adding other agents, including other antibody drug conjugates, to further enhance responses.
  • Sequencing: The role of EV plus Pembro in sequencing with chemotherapy, FGFR inhibitors, and other antibody drug conjugates is also a necessary research focus.
Ongoing research will determine how to further optimize and build upon this transformative combination therapy. Some ongoing clinical trial efforts are highlighted below:

Ongoing Trials with Enfortumab Vedotin plus Pembrolizumab Refinements and Additions

  • Enfortumab Vedotin Schedule De-escalation with and without Pembrolizumab (NCT05923190)
  • Sacituzumab Govitecan Addition to Enfortumab vedotin plus Pembrolizumab (NCT04724018)
  • KEYMAKER-U04 – Sacituzumab Tirumotecan plus Enfortumab vedotin with and without Pembrolizumab (NCT06483334)
Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

  1. Von der Maase H, et al. Gemcitabine and Cisplatin Versus Methotrexate, Vinblastine, Doxorubicin, and Cisplatin in Advanced or Metastatic Bladder Cancer: Results of a Large, Randomized, Multinational, Multicenter, Phase III Study. J Clin Oncol 2000; 18(17):3068-3077.
  2. Powles T, et al. Enfortumab Vedotin and Pembrolizumab in Untreated Advanced Urothelial Cancer. N Engl J Med. 2024; 390(10):875-888. doi: 10.1056/NEJMoa2312117.
  3. Rosenberg JE, et al. Enfortumab Vedotin Plus Pembrolizumab in Previously Untreated Advanced Urothelial Cancer. J Clin Oncol. 2023; 41(6):1005–1015.
  4. Klumper N, et al. NECTIN4 Amplification Is Frequent in Solid Tumors and Predicts Enfortumab Vedotin Response in Metastatic Urothelial Cancer. J Clin Oncol. 2024; 42(20):2446–2455.