Kidney cancer and urothelial carcinoma are among the most common malignancies of the urinary system and are known for their strong immunogenicity. This characteristic theoretically makes them ideal candidates for immune checkpoint inhibitors. However, results from multiple phase III randomized controlled trials (RCTs) have failed to demonstrate a significant overall survival (OS) benefit for immunotherapy in these cancers. The question remains: how should clinicians approach immunoadjuvant therapy in clinical practice? During the recent ASCO GU Annual Meeting, leading urologic oncology experts from MD Anderson Cancer Center shared their insights.

Key Findings from Clinical Trials

The KEYNOTE-564 trial represents the first phase III clinical study to achieve positive results for clear cell renal cell carcinoma (ccRCC), demonstrating that pembrolizumab adjuvant therapy improves both disease-free survival (DFS) and overall survival (OS).

For urothelial carcinoma (UC), the CheckMate-274 and AMBASSADOR studies have shown that adjuvant immunotherapy with nivolumab and pembrolizumab, respectively, improves DFS compared to placebo. However, the final OS analysis is still pending for both trials—OS is a co-primary endpoint in the AMBASSADOR trial and a secondary endpoint in CheckMate-274.

Given the potential toxicity associated with immunotherapy and its implications for future treatment in metastatic disease, it is critical to weigh the risks and benefits carefully. In high-risk patients identified during surgical resection, treatment decisions should be made collaboratively with the patient, balancing the risks and benefits while considering patient preferences. Future research will need to focus on identifying predictive biomarkers and refining treatment strategies for more precise therapeutic approaches.

Shifting Clinical Practice with Pembrolizumab Adjuvant Therapy

Based on the KEYNOTE-564 trial, pembrolizumab adjuvant therapy has been approved and has reshaped clinical practice in RCC. By contrast, the treatment of muscle-invasive urothelial carcinoma (MIUC) has long relied on neoadjuvant chemotherapy and cisplatin-based adjuvant therapy. The AMBASSADOR trial (evaluating pembrolizumab) and CheckMate-274 trial (evaluating nivolumab) have demonstrated progress in adjuvant immunotherapy for this patient population. Experts from MD Anderson Cancer Center illustrated their treatment strategies with two case studies.

Case Studies in Immunoadjuvant Therapy

A 52-year-old male patient underwent radical left nephrectomy, with pathology confirming a 10.5 cm ccRCC tumor (Fuhrman grade IV) with sarcomatoid dedifferentiation, renal vein invasion, and necrosis. No malignancy was detected in the three resected lymph nodes.

A 62-year-old female patient with muscle-invasive bladder cancer received four cycles of dose-dense MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) followed by radical cystectomy and bilateral pelvic lymph node dissection. Pathology showed ypT3N1 disease with one of 22 lymph nodes involved.

According to the ASSURE nomogram, the first patient’s ccRCC was classified as high-risk, with an estimated three-year DFS rate of 32% and an early progression risk of 46.5%. For the UC patient, the International Bladder Cancer Nomogram Collaboration model estimated a five-year DFS rate of 28%. Both patients faced a significant risk of recurrence and met the inclusion criteria for immunoadjuvant therapy trials.

Treatment Considerations for ccRCC

For the first patient, experts discussed the available evidence supporting pembrolizumab’s role in improving DFS and OS, the impact of sarcomatoid features on disease progression, and the poor outcomes associated with tyrosine kinase inhibitors in metastatic RCC with sarcomatoid differentiation. The role of combination immunotherapy in such patients was also considered.

If surveillance was chosen instead of pembrolizumab, experts examined the potential use of nivolumab plus ipilimumab upon relapse. The CheckMate-214 trial, with over eight years of follow-up, has demonstrated long-term efficacy of this regimen. In subgroup analyses, nivolumab plus ipilimumab showed an objective response rate (ORR) of approximately 61% and a complete response (CR) rate of 23% at five years in patients with sarcomatoid features, with a median progression-free survival (PFS) of 26.5 months and a median OS of 48.6 months.

Starting immunotherapy now could impact future treatment options in case of recurrence. No trial has directly compared upfront PD-1 monotherapy with subsequent PD-1 plus CTLA-4 blockade. However, clinical data suggest that patients who develop resistance to PD-1 inhibitors respond less effectively to subsequent ipilimumab-based combination therapy. Given this, a cautious approach involving close surveillance and reserving nivolumab plus ipilimumab for relapse remains a reasonable strategy, provided the patient is fully engaged in shared decision-making.

Additionally, the four-year DFS analysis of KEYNOTE-564 revealed that 56% of patients in the placebo group remained recurrence-free. This raises concerns that widespread adoption of adjuvant therapy might expose more than half of patients to potential pembrolizumab-related toxicity without clear benefit. Experts have observed that in patients with high-risk features such as sarcomatoid differentiation, early administration of pembrolizumab within four to six weeks post-nephrectomy may not detect occult metastatic disease. However, within three to four months, some patients progress to overt metastatic disease.

Bladder Cancer Treatment Strategies

High Risk of Recurrence and the Role of Circulating Tumor DNA

For the bladder cancer case described, the patient has demonstrated resistance to cisplatin, indicating a significantly high risk of rapid recurrence, potentially exceeding the estimates from the International Bladder Cancer Nomogram Collaboration model. One emerging prognostic tool for post-cystectomy residual disease monitoring is circulating tumor DNA (ctDNA), which is currently being analyzed in clinical trials exploring both escalation and de-escalation treatment strategies.

Considerations for Adjuvant Immunotherapy

When evaluating adjuvant immunotherapy, its potential value in metastatic disease must also be taken into account. Retrospective analyses of long-term follow-up data from the KEYNOTE-052 and LEAP-011 trials, with a median follow-up of 56.3 months, suggest that pembrolizumab monotherapy yields an objective response rate (ORR) of 25%–33% in frail patients who are unfit for or decline platinum-based chemotherapy, including those with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, age 80 or older, or renal impairment. Among those who achieved an objective response, approximately 12%–34% maintained their response at 48 months, representing less than 15% of the total study population. However, in the KEYNOTE-361 trial, pembrolizumab monotherapy demonstrated a low 18-month progression-free survival (PFS) rate of 19%.

Treatment Options for Disease Recurrence

If the patient experiences disease recurrence, post-adjuvant therapy treatment options must be carefully considered. The impact of prior adjuvant immunotherapy on the efficacy of enfortumab vedotin (EV) combined with pembrolizumab, which is currently the preferred first-line regimen for metastatic UC, remains uncertain.

At the 2025 ASCO GU Annual Meeting, data from the UNITE cohort showed that among 43 patients previously treated with immunotherapy, enfortumab vedotin plus pembrolizumab achieved an ORR of 48% (95% CI: 33%–66%), with a median PFS of 6.9 months and a median OS of 15.4 months. These results align with previous findings from the UNITE study, where a cohort of 304 patients treated with enfortumab vedotin achieved an ORR of 52%, a median PFS of 6.8 months, and a median OS of 14.4 months. However, these outcomes were notably lower than those observed in first-line EV plus pembrolizumab treatment in the EV-302 trial, where the ORR was 67.7% and median PFS was 12.5 months.

Additionally, five-year follow-up data from the EV-103 study demonstrated that 47% of patients who achieved an objective response (ORR: 73%) remained progression-free at five years. If a patient progresses rapidly after adjuvant immunotherapy, alternative treatment options must be considered. These include enfortumab vedotin monotherapy, erdafitinib for patients with FGFR2/3 alterations, or trastuzumab deruxtecan (T-DXd) for HER2-positive (IHC 3+) UC.

The Impact of OS Data from CheckMate-274 and AMBASSADOR

In the CheckMate-274 trial, OS was designated as a secondary endpoint, whereas in the AMBASSADOR trial, both OS and DFS were co-primary endpoints in the intention-to-treat population. The interim OS analysis from CheckMate-274 has not yet reached the pre-specified significance threshold, and the final analysis is still pending.

The AMBASSADOR trial, with a median follow-up of 44.8 months, reported no OS benefit after one year of pembrolizumab adjuvant therapy. One possible explanation is that patients who withdrew early from the trial later received nivolumab. The increased withdrawal rate introduces a risk of informative censoring, which may bias the interpretation of the trial results.

Balancing Treatment Decisions in Clinical Practice

In clinical practice, it remains crucial to weigh the benefits and risks of early immunotherapy. The majority of patients with localized disease require careful monitoring to determine the optimal timing of intervention while preserving the most effective therapies for micrometastatic or recurrent disease.

Future advancements in biomarker-driven treatment strategies will help refine decision-making, including ctDNA for UC and KIM-1 for RCC, allowing for more personalized and adaptive treatment approaches. Additionally, multi-stage treatment strategies and improved risk stratification models will be essential in achieving precision oncology for these patients.

Until these innovations become standard practice, treatment decisions should involve shared decision-making between physicians and patients, ensuring that the potential benefits, risks, and individual patient preferences are carefully considered before initiating adjuvant immunotherapy.

---

• Matthew T. Campbell

Associate Professor and Associate Medical Director, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center

• Mohammad Jad Moussa

Postdoctoral Research Fellow, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center

• Pavlos Msaouel

Assistant Professor, Department of Genitourinary Medical Oncology and Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center

• Nizar M. Tannir

Professor, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center

• Omar Alhalabi

Assistant Professor, Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center