As our understanding of these novel therapies grows, it becomes evident that there are nuanced aspects of treatment selection and response that require further investigation. In 2023, new findings from the Checkmate-901 (CM-901) and EV-302 trials introduced additional layers of complexity to the treatment framework. Despite previous negative outcomes from similar studies, the CM-901 trial highlighted the superiority of combining immune checkpoint inhibitors (ICI) with chemotherapy (CTX) compared to chemotherapy alone. The EV-302 trial also produced favorable results, demonstrating the enhanced efficacy of enfortumab vedotin plus pembrolizumab (EV-P) over standard chemotherapy. As a result, EV-P has now emerged as the preferred first-line therapy.
In this context, we aimed to evaluate the relative efficacies of various novel therapeutic regimens in mUC. The study included 5,449 patients from six randomized controlled trials, with 3,255 receiving either ICI monotherapy, antibody-drug conjugate, or combination therapy. The results demonstrated that the combination of EV-P provided the most substantial reduction in the risk of death (HR 0.47 [95% CrI: 0.38, 0.58]), followed by avelumab monotherapy (HR 0.69 [95% CrI: 0.56, 0.86]). This benefit was observed regardless of PD-L1 status. Similarly, EV-P showed the most significant improvement in progression-free survival (PFS) (HR 0.45 [95% CrI: 0.38, 0.54]), again followed by avelumab monotherapy (HR 0.62 [95% CI: 0.52, 0.75]).
In addition to its role in metastatic disease, immunotherapy is also being explored in earlier stages of urothelial carcinoma, particularly in neoadjuvant and adjuvant settings for patients undergoing radical cystectomy. Neoadjuvant immunotherapy aims to reduce tumor burden before surgery and potentially eliminate micrometastases, while adjuvant immunotherapy seeks to eradicate residual disease and prevent recurrence after surgery. Several ongoing clinical trials are investigating the efficacy of immune checkpoint inhibitors in these settings. For instance, the PURE-01 trial demonstrated promising results with pembrolizumab as neoadjuvant therapy, showing significant pathological complete response rates, especially in patients with high PD-L1 expression. Similarly, the IMvigor010 trial explored atezolizumab in the adjuvant setting, and while it did not meet its primary endpoint of disease-free survival in the overall population, subset analyses suggested potential benefits in certain patient groups. These studies highlight the potential of immunotherapy to improve outcomes in localized muscle-invasive bladder cancer, potentially sparing some patients from radical cystectomy or enhancing the efficacy of surgery.
Our study highlights several important areas for future research and clinical consideration. These include the need for biomarker refinement beyond PD-L1 expression, the potential of circulating tumor DNA (ctDNA) analysis, exploration of novel combination strategies, optimization of treatment sequencing, and evaluation of health economics and quality of life outcomes. Additionally, the impressive efficacy of some regimens in the metastatic setting raises questions about their potential role in earlier disease stages.
In PD-L1 positive tumors, both EV-P and avelumab demonstrated superiority across most efficacy endpoints. However, the benefit observed in PD-L1 negative patients suggests that a subgroup of patients may show differential responses to various combination therapies. This finding may lead to the discovery of novel mechanisms in mUC pathophysiology and treatment resistance.
Recent developments in immunotherapy for urothelial carcinoma include several ongoing clinical trials exploring novel combination strategies. Multiple single-arm phase 2 trials are investigating avelumab in combination with agents such as talazoparib, lurbinectedin, and copanlisib, while another study is examining maintenance ipilimumab plus nivolumab. Additionally, three randomized phase 2 trials are evaluating various combination maintenance immunotherapy regimens, including the PRESERVE 3 trial (trilaciclib plus chemo followed by trilaciclib plus avelumab maintenance), the JAVELIN Bladder Medley study (avelumab with or without sacituzumab govitecan, M6223, or NKTR-255), and the TROPHY U-01 trial (exploring combinations with sacituzumab govitecan and different immunotherapies). The phase 3 MAIN-CAV trial, investigating maintenance avelumab with or without cabozantinib, represents the most advanced study in this area. These trials primarily focus on progression-free survival as their primary endpoint and aim to further optimize immunotherapy-based treatment strategies for urothelial carcinoma patients.
As the field of mUC treatment continues to evolve, close collaboration between oncologists, urologists, and researchers will be essential to optimize patient care and drive further innovations. The promising results of novel combinations like EV-P provide a strong foundation for future research and clinical practice in the treatment of metastatic urothelial carcinoma. However, it's important to note that these new regimens may not yet be accessible to all patients due to cost limitations or availability worldwide.
In conclusion, this network meta-analysis provides valuable insights into the relative efficacies of various novel therapeutic regimens in mUC. The superior efficacy of EV-P suggests that it should be considered as a new standard of care in first-line treatment for mUC, where available. However, in cases where EV-P is not accessible, other ICI-based combinations or monotherapies may still offer significant benefits over traditional chemotherapy approaches. Future research should focus on refining biomarker strategies, exploring novel combinations, and addressing the challenges of treatment sequencing and accessibility to ensure optimal outcomes for all patients with mUC.
Written by:
- Gal Saffati, MD, Scott Department of Urology, Baylor College of Medicine, Houston, TX
- David E. Hinojosa-Gonzalez, MD, Scott Department of Urology, Baylor College of Medicine, Houston, TX