Editor’s Note: The 2026 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU 2026) has successfully concluded. As one of the premier global academic meetings in genitourinary oncology, the conference showcased multiple landmark studies that are reshaping clinical practice worldwide. During the meeting, Oncology Frontier – UroStream invited Professor Avivit Peer from Rambam Health Care Campus in Haifa to discuss key clinical advances and emerging strategies in advanced urothelial carcinoma (UC), with a particular focus on insights from the Keymaker-U04B study.
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Oncology Frontier: Targeted immunotherapy combinations have dramatically improved survival outcomes in advanced urothelial carcinoma. How do you assess the clinical value of this strategy?
Professor Avivit Peer: This year’s ASCO GU meeting highlighted several exciting advances. Among them, the combination of enfortumab vedotin (EV) plus pembrolizumab—the EVPembro regimen—stands out as a true milestone for patients with both localized and advanced or metastatic urothelial carcinoma. It could even be described as the “holy grail” of treatment in this disease.
The results of this regimen are practice-changing and are fundamentally reshaping our clinical approach across disease stages. We have now entered an era in which EVPembro can be applied broadly across the entire spectrum of urothelial carcinoma. This represents a particularly exciting moment in genitourinary oncology.
Importantly, this regimen offers new hope for patients with advanced disease by significantly prolonging overall survival while also improving quality of life. It has effectively redefined the therapeutic landscape of advanced urothelial carcinoma.
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Oncology Frontier: You recently presented findings from the Keymaker-U04B study. Could you outline the study background and its clinical implications?
Professor Avivit Peer: The Keymaker-U04B study was designed to address a key clinical challenge: although EVPembro is highly effective, not all patients derive benefit. Approximately 10% of patients experience primary disease progression, while another 20% achieve only stable disease. Even among responders, more than half eventually develop acquired resistance.
With this in mind, we aimed to further enhance treatment efficacy by targeting fundamental mechanisms of tumor progression and resistance. One key strategy was to augment the activity of immune checkpoint inhibitors.
Among mechanisms of immune escape, LAG-3 and TIGIT have emerged as particularly important targets. LAG-3 is often co-expressed with PD-L1 and plays a central role in T-cell exhaustion within the tumor microenvironment, a major driver of resistance. TIGIT, expressed on tumor cells and antigen-presenting cells, is also closely associated with T-cell exhaustion and regulatory T-cell function.
Targeting these pathways in combination is therefore biologically rational. Early studies suggested that this approach might enhance antitumor activity without substantially increasing toxicity. For comparison, adding ipilimumab (an anti–CTLA-4 agent) may improve efficacy but is associated with significantly higher toxicity, whereas LAG-3 and TIGIT inhibition was expected to offer a more favorable balance.
Keymaker-U04B (NCT05845814) is a randomized, open-label, phase I/II umbrella trial presented at ASCO GU 2026. It evaluated whether adding a dual LAG-3/TIGIT inhibitor to first-line EVPembro could further improve outcomes in advanced urothelial carcinoma.
Unfortunately, the results were negative. The addition of either LAG-3 or TIGIT inhibitors significantly increased treatment-related toxicity, leading to higher discontinuation rates, without providing meaningful clinical benefit.
This study delivers an important message: EVPembro remains the benchmark (“holy grail”) in advanced urothelial carcinoma, and the triplet combination strategy tested here did not achieve an acceptable benefit–risk profile.
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Oncology Frontier: Despite the strong efficacy of EV plus pembrolizumab, some patients do not respond or eventually progress. What treatment options are available after first-line failure?
Professor Avivit Peer: Managing patients who progress after first-line EVPembro is one of the most pressing challenges we face. While there is no universally accepted global standard, several important options are available.
First, for patients with FGFR2/3 alterations, erdafitinib represents a key targeted therapy. Additionally, data from Memorial Sloan Kettering Cancer Center show that platinum-based chemotherapy after EVPembro can achieve an objective response rate of approximately 30%–40%, with a median duration of response of 4–5 months, making it a reasonable later-line option.
Second, HER2 testing is becoming increasingly important. HER2 is emerging as a critical therapeutic target in advanced urothelial carcinoma. For patients with HER2 overexpression (IHC 3+), fam-trastuzumab deruxtecan (T-DXd), which has been approved by the FDA, is a rational treatment option. As an antibody–drug conjugate with a distinct target and payload, it provides a novel therapeutic pathway.
In addition, numerous ongoing clinical trials are evaluating next-generation ADCs with alternative targets and payloads, aiming to overcome resistance and restore treatment sensitivity.
In summary, while several treatment options exist, I strongly believe that participation in clinical trials remains one of the best choices for these patients. Clinical trials provide access to innovative therapies and offer the potential for improved outcomes and renewed hope.
Professor Avivit Peer
