Narrative review on immune-related adverse events (irAEs) of immune checkpoint inhibitors in the adjuvant therapy of urological cancers

Introduction

Transition from metastatic to earlier-stage applications

The advent of immune checkpoint inhibitors (ICIs) targeting programmed-death receptor 1 (PD-1), programmed-death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) has ushered in a transformative era in cancer immunotherapy. In urological malignancies such as urothelial carcinoma (UC) and renal cell carcinoma (RCC), ICIs have delivered significant therapeutic advances in metastatic and palliative settings by reinvigorating immune responses against tumours previously adept at evading detection. Building on their success in late-stage disease, ICIs are now being actively explored in earlier disease contexts, particularly in the adjuvant setting, where the intent is curative (1).

Urological cancers have long stood out as promising candidates for immunotherapy. The breakthrough came with the bacillus Calmette-Guerin (BCG) vaccine approved by the Food and Drug Administration (FDA), the first immunotherapeutic agent to make a clinical impact, for non-muscle-invasive bladder cancer. Following this, sipuleucel-T carved out a role for castration-resistant prostate cancer. Meanwhile, the broader immunotherapy landscape was rapidly evolving and first expanded with the approval of ipilimumab, an anti-CTLA-4 antibody for melanoma, followed by the clinical integration of anti-PD-1 agents (nivolumab and pembrolizumab) and anti-PD-L1 agents (atezolizumab, avelumab, durvalumab) across various tumour types. Despite their therapeutic promise, ICIs are associated with a spectrum of immune-related adverse events (irAEs), reflecting unintended immune activation that may affect multiple organ systems, most commonly the skin, gastrointestinal tract, endocrine glands, liver, and lungs. Anti-CTLA-4 agents tend to elicit more severe, dose-dependent irAEs, particularly colitis, while anti-PD-1 therapies are more frequently associated with pneumonitis, and anti-PD-L1 agents with infusion reactions (2).

In the adjuvant setting, the rationale for ICI use lies in the eradication of micrometastatic disease following definitive surgery, thereby lowering recurrence risk in patients with high-risk features. Landmark clinical trials such as CheckMate-274 and KEYNOTE-564 have established compelling evidence for this approach, demonstrating the efficacy of nivolumab in UC and pembrolizumab in RCC (3,4). These trials enrolled heterogeneous patient cohorts, including those with or without prior neoadjuvant chemotherapy, capturing the diversity encountered in real-world clinical practice.

In parallel with clinical progress, an expanding body of literature has deepened our understanding of how ICIs are reshaping systemic therapy paradigms in urological cancers. Recent investigations have underscored the relevance of immune checkpoint blockade in both traditional and emerging therapeutic settings. For instance, studies exploring perioperative immunotherapy have illuminated opportunities to personalise treatment pathways based on molecular risk profiles and surgical timing, while others have advanced the integration of biomarkers and immunogenomic signatures into trial design. This evolving body of evidence has helped reframe the role of ICIs not merely as agents of disease control but as potential modulators of long-term oncologic outcomes. Key contributions in this space, from analyses of novel therapeutic sequencing to trials evaluating early intervention strategies, demonstrate the momentum toward more precise, risk-adapted application of ICIs in genitourinary (GU) malignancies (5-10).

Beyond UC and RCC, early-phase data suggest that immunotherapy may hold promise in rarer urological cancers, including select subsets of prostate, penile, and testicular malignancies, particularly those characterised by mismatch repair deficiency (dMMR) or high tumour mutational burden (TMB) (11,12). This shift from treating overt metastatic disease to intercepting relapse in surgically resected patients marks a pivotal inflection point in GU oncology—one that demands careful navigation of therapeutic efficacy, safety, and long-term survivorship.

The current analysis provides findings supporting the use of adjuvant nivolumab therapy in UC and adjuvant pembrolizumab therapy in RCC, aligning with current treatment guidelines. We present this article in accordance with the Narrative Review reporting checklist (available at https://cco.amegroups.com/article/view/10.21037/cco-25-27/rc).

Methods

We conducted a targeted literature search between 24 September 2024 and 25 January 2025 to identify pertinent studies on ICIs used in the adjuvant setting for urological malignancies. Five electronic databases—PubMed, Embase, Web of Science, Scopus, and the Cochrane Library—were searched, supplemented by hand-searching reference lists from relevant review articles and examining abstracts from major oncology conferences [e.g., American Society of Clinical Oncology (ASCO), European Society for Medical Oncology (ESMO)] within the same timeframe.

Our search incorporated both Medical Subject Headings (MeSH) terms and free-text keywords (e.g., “Immune Checkpoint Inhibitors”, “adjuvant immunotherapy”, “urothelial carcinoma”, “renal cell carcinoma”, “immune-related adverse events”). Articles were eligible if they: (I) focused on phase I–III clinical trials, systematic reviews, meta-analyses, or large observational cohorts involving ICIs in the adjuvant setting for GU cancers; (II) were published in English or available in an English translation between January 2014 and January 2025; and (III) provided data on efficacy, safety, or immune-related toxicities. We excluded case reports, small case series with fewer than ten patients, non-English-language studies without translations, and editorials or commentaries lacking original data.

Titles and abstracts were initially screened by a single reviewer according to predefined eligibility criteria. Relevant full-text articles were then retrieved and assessed to confirm final inclusion. The reference lists of these articles were additionally hand-searched to identify any studies not captured by the electronic database search. Data extracted from each included study encompassed patient population characteristics, study design, interventions, key efficacy outcomes, and reported irAEs. The complete search strategy is outlined in Table 1 and Table S1.

Following selection, all included publications were appraised for relevance, study design, and quality of evidence. Information regarding irAEs was collated, paying special attention to event type, frequency, severity, and clinical management. The final synthesis aimed to identify emerging patterns in adjuvant ICI efficacy, toxicity profiles, and practical implications for patient care in urological oncology.

Findings

Importance of understanding irAEs in the adjuvant setting

The use of ICIs in the adjuvant setting presents unique challenges, particularly regarding irAEs. These toxicities arise from immune system hyperactivation, with collateral damage to normal organs, particularly endocrine, dermatologic, and gastrointestinal systems. Unlike metastatic disease, where irAEs are often justified by clear therapeutic benefits, the risk-benefit calculus in the adjuvant setting is more complex. Patients without detectable disease may face significant morbidity from irAEs without assured survival benefits, necessitating a nuanced understanding of the risks involved (13).

Adjuvant trials have reported varying irAE incidence and severity compared to metastatic settings. Delayed-onset endocrine toxicities, such as hypothyroidism and adrenal insufficiency, are frequently observed in adjuvant therapy. Long-term follow-up studies suggest these irAEs may persist indefinitely, imposing chronic health burdens (14). The challenge is further compounded by the limited availability of predictive biomarkers for irAE susceptibility and the necessity for continuous monitoring in a survivorship setting. Detailed mechanistic insights and clinical evaluations of irAE profiles are essential for optimising patient selection and balancing therapeutic efficacy with safety (15).

Following meta-analysis on side effects of immunotherapy, including 87 trials, encompassing 14,899 patients across 101 treatment arms, reported a treatment-associated mortality rate of 0.94%. Among 10,723 patients, immune-related deaths were observed in 28 cases (0.26%). The most common causes of treatment-related mortality were pneumonitis (9.3%), pneumonia (7.9%), respiratory failure (7.1%), sepsis (6.4%), unknown causes (6.4%), cardiac arrest (5.7%), and bowel perforation (5%). The primary causes of immune-related deaths included pneumonitis (35.7%), hepatic failure (10.7%), hepatitis (7.1%), myocarditis (7.1%), and myasthenia gravis (7.1%). The most frequently reported any-grade irAEs included rash (13.8%), hypothyroidism (11%), and diarrhoea (10.4%). The most common grade ≥3 irAEs were diarrhoea (2.7%), severe skin reactions (2.2%), and increased alanine aminotransferase levels (2%) (16).

Role of ICIs in specific urological cancers

UC

UC has been a pivotal focus of ICI research, particularly given the limited options for patients with platinum-refractory or cisplatin-ineligible disease. Several phase III trials have explored ICIs in the adjuvant setting, producing both encouraging and inconclusive results.

CheckMate-274

CheckMate-274 is a landmark phase III trial evaluating adjuvant nivolumab in high-risk muscle-invasive urothelial carcinoma (MIUC) following radical surgery. The study enrolled 709 patients stratified based on PD-L1 expression levels (≥1%) (3). Eligible patients had either received neoadjuvant cisplatin-based chemotherapy (43.3%) or were ineligible or declined adjuvant cisplatin-based chemotherapy. Radical resection had been completed within 120 days, with patients confirmed to be disease-free within four weeks of randomization.

The trial demonstrated a significant improvement in disease-free survival (DFS) in the nivolumab arm, with a median DFS of 20.8 months vs. 10.8 months in the placebo group [hazard ratio (HR) 0.70; P<0.001]. However, PD-L1 expression has not been consistently validated as a reliable biomarker in UC, necessitating cautious interpretation (3,17). Endocrine toxicities, particularly thyroiditis and adrenal insufficiency, were among the most common irAEs, often requiring lifelong management. The trial reported a grade ≥3 irAE rate of 18%, with 10% of patients discontinuing treatment due to toxicity. Two treatment-related deaths occurred in the nivolumab group due to pneumonitis and bowel perforation (18,19).

IMvigor010

In contrast, the IMvigor010 trial, assessing adjuvant atezolizumab in a similar high-risk MIUC population (particularly at high risk for recurrence) with an expected 5-year recurrence risk of approximately 50%, adjuvant chemotherapy or radiation therapy for UC following surgical resection was not allowed, did not demonstrate a DFS benefit. The median DFS was 19.4 months in the atezolizumab group vs. 16.6 months in the observation arm [hazard ratio (HR) 0.89; P=0.244] (10). Unlike CheckMate-274, this trial utilised a higher PD-L1 expression cut-off, potentially excluding patients who might have benefited from ICI therapy. Importantly, there was no observed overall survival (OS) benefit, raising concerns about the risk-benefit ratio in light of long-term toxicities (20,21).

Exploratory analyses suggested that circulating tumour DNA (ctDNA) may identify patients more likely to benefit from adjuvant atezolizumab. These findings highlight ctDNA as a promising biomarker for personalised therapy in UC, warranting further validation (22).

One out of 114 patients (<1%) in the atezolizumab arm died as a result of a treatment-related adverse event (acute respiratory distress syndrome) (23). A detailed comparison of irAE profiles and trial outcomes is presented in Table 2.

Ongoing trials: AMBASSADOR and NIAGARA

The AMBASSADOR trial (evaluating pembrolizumab) and the NIAGARA trial (investigating durvalumab in perioperative settings) aim to further elucidate the role of ICIs in UC. Both trials are designed to address limitations in earlier studies by incorporating longer follow-up for OS endpoints and by exploring biomarker-driven stratification, including PD-L1 expression and ctDNA profiling, to better define responders. Preliminary results from NIAGARA suggest perioperative strategies integrating neoadjuvant and adjuvant ICIs may enhance efficacy by addressing residual disease earlier in the treatment continuum. Comprehensive outcome data on DFS and OS from these trials are awaited (24,25).

The AMBASSADOR trial reported a median DFS of 29.6 months with pembrolizumab compared to 14.2 months with observation (HR 0.73; P=0.0027). Grade 3 or higher adverse events occurred in 50.7% of patients in the pembrolizumab arm, with five treatment-related deaths attributed to respiratory failure, multi-organ failure, sepsis, and unspecified causes (26). These early safety signals reinforce the importance of correlating clinical benefit with validated biomarkers to avoid overtreatment in lower-risk populations.

RCC

In RCC, the advent of ICIs has significantly shifted therapeutic paradigms, particularly in combination with tyrosine kinase inhibitors (TKIs) in advanced disease. However, adjuvant applications remain an area of active investigation.

KEYNOTE-564

The KEYNOTE-564 trial provided support for the use of adjuvant pembrolizumab monotherapy as a standard of care for patients with RCC at an increased risk of recurrence after nephrectomy.

KEYNOTE-564 is a pivotal phase III trial evaluating pembrolizumab in patients with high-risk localised RCC. The trial demonstrated a marked DFS improvement, with a median DFS of 32.4 vs. 22.1 months in the placebo arm (HR 0.68; P=0.002) (4). Importantly, stringent inclusion criteria focusing on clear-cell histology ensured a homogenous study population, improving the reliability of results. Endocrine toxicities, particularly hypothyroidism, were among the most reported irAEs, with grade ≥3 events occurring in 7.5% of patients (4). Unlike earlier findings, updated results from KEYNOTE-564 demonstrate a statistically significant OS benefit with adjuvant pembrolizumab [HR 0.62; 95% confidence interval (CI), 0.44–0.87; P=0.005] (26), strengthening its role in high-risk RCC. The clinical significance of this OS benefit must still be weighed against the potential for chronic immune-related toxicities, particularly in lower-risk patients (15,27). No deaths were attributed to pembrolizumab therapy (27).

IMmotion010

Similar to IMvigor010 in UC, the IMmotion010 trial evaluating atezolizumab in RCC failed to achieve significant DFS benefits (HR 0.93; P=0.533). These results highlight variability in adjuvant ICI efficacy and underscore the need for robust biomarker development to guide patient selection (28).

Prostate, penile, and testicular cancers

Prostate cancer

Prostate cancer’s low immunogenicity has limited the success of ICIs due to highly reactive stroma densely populated by regulatory T cells with immunosuppressive tendencies. These characteristics make it a “cold tumour” that is not easy to treat with immunotherapy (25). However, subsets of patients with dMMR or high TMB have demonstrated significant responses, as evidenced by the KEYNOTE-199 trial evaluating pembrolizumab in metastatic castration-resistant prostate cancer (mCRPC) (29).

Penile and testicular cancers

Early-phase studies suggest potential efficacy of ICIs in human papillomavirus (HPV)-associated penile cancers and testicular germ cell tumours with high PD-L1 expression. However, robust clinical data are lacking, and irAE profiles in these populations remain underexplored (30).

Comparison of irAEs: adjuvant vs. metastatic settings

Biological mechanisms

Key mechanisms driving irAE differences include tumour burden–mediated immune activation and prior therapy–induced immune priming. Adjuvant irAEs frequently reflect autoimmune phenomena due to minimal residual disease, while metastatic irAEs are often exacerbated by high systemic inflammation and neoantigen loads (31).

Timing and management

Adjuvant irAEs frequently exhibit delayed onset and prolonged duration, necessitating extended monitoring and survivorship care. For example, hypothyroidism emerging months after treatment cessation highlights the need for sustained follow-up and interdisciplinary management strategies (32). Therefore, the late manifestation of the aforementioned side effects challenges traditional follow-up models and necessitates evolving care pathways that incorporate long-term endocrine, dermatologic, and rheumatologic surveillance.

Clinical implications

Risk-benefit analysis

While adjuvant ICIs improve DFS in high-risk patients, the absence of consistent OS benefits across trials underscores the need for critical appraisal of their long-term value. Balancing these gains against the potential for chronic or life-altering irAEs is essential, particularly in patients with no evidence of active disease. Biomarker integration, including PD-L1 expression and ctDNA, may enhance patient selection and mitigate unnecessary exposure to toxicity. (33).

Survivorship and quality of life

The chronic nature of irAEs, such as hypothyroidism or adrenal insufficiency, demands survivorship frameworks that go beyond toxicity management. Incorporating patient-reported outcome measures (PROMs) into clinical trials has enabled more nuanced evaluations of therapy impact, particularly on fatigue, emotional well-being, and return to baseline function (34). Examples from KEYNOTE-564 and CheckMate-274 demonstrate the value of longitudinal PROMs in capturing quality of life beyond conventional clinician-reported metrics. This underscores the need for PROMs to become a standard component of ICI trial design, particularly in the adjuvant setting.

Emerging paradigms

This review highlights a rapidly evolving and complex area of immune-oncology. The potential of adjuvant ICIs lies not only in reducing recurrence risk but also in refining long-term outcomes in urological cancers. However, key knowledge gaps remain, particularly regarding patient selection, long-term toxicity, and the integration of predictive biomarkers (35). Over the next five years, we expect this field to shift from “one-size-fits-all” adjuvant regimens to a more personalised approach, leveraging tools such as ctDNA, molecular profiling, and adaptive trial designs. These will help balance efficacy with safety and avoid overtreatment. From a personal perspective, navigating these trade-offs in asymptomatic, surgically treated patients will require ongoing dialogue between clinicians, researchers, and patients to ensure meaningful, patient-centred progress.

Ethical and economic considerations

Cost-effectiveness analyses incorporating quality-adjusted life years (QALYs) and initiatives to ensure equitable access to novel therapies are essential. Collaborative efforts involving stakeholders are needed to address disparities and optimise patient-centred outcomes (36).

Limitations and future directions

This review is limited by its narrative methodology, which does not employ the statistical rigor of a systematic review or meta-analysis. As a consequence, while the synthesis captures key themes across landmark trials, it is open to selection bias and may overrepresent certain findings. Complicating the picture for comparative interpretation are the inclusion criteria of the trials, the heterogeneity of the studies themselves, and the inconsistent reporting of outcomes. For example, the trials differ in their PD-L1 stratification thresholds and in how they define irAEs. Although most of the available data focus on DFS, the results for OS are either immature or absent. This raises questions about the long-term value of ICO therapy given as an adjuvant treatment. There is also a lack of standardized endpoints across trials, particularly regarding duration and severity of chronic irAEs, limiting cross-study comparability.

Follow-up studies should concentrate on the quantitative synthesis of trial outcomes, particularly cohesive analyses of irAE incidence, recurrence-free survival across risk groups, and biomarker-defined subpopulations, as these are the key metrics. Standardisation of immune-related toxicity grading, integration of ctDNA for minimal residual disease detection, and validation of predictive biomarkers, such as TMB and immune gene expression signatures, will be crucial in refining patient selection and treatment duration. Additionally, the incorporation of real-world data, post-marketing surveillance, and patient registry analyses will be essential to capture late-onset toxicities, economic impact, and quality of life outcomes that are underrepresented in prospective trials.

Conclusions

Adjuvant ICIs represent a transformative step in urological oncology, offering meaningful reductions in recurrence risk for select high-risk patients. Their integration, however, introduces complex trade-offs between efficacy, long-term toxicity, and quality of life.

Maximizing the impact of these therapies will require biomarker-guided patient selection and molecular risk profiling, alongside survivorship care attuned to chronic irAEs. Success will depend on multidisciplinary coordination, thoughtful trial design, and equitable access to ensure these therapies deliver not only survival benefit but also enduring value for patients.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://cco.amegroups.com/article/view/10.21037/cco-25-27/rc

Peer Review File: Available at https://cco.amegroups.com/article/view/10.21037/cco-25-27/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://cco.amegroups.com/article/view/10.21037/cco-25-27/coif). G.L.B. serves as an unpaid editorial board member of Chinese Clinical Oncology from August 2024 to July 2026. G.L.B. reports personal fees from advisory boards (Accord, AstraZeneca, Amgen, and Merck); speaker bureaus (Astellas, AstraZeneca, Amgen, Bayer, Merck, and Pfizer); patents: n. 4 patents with ST Microelectronics; and travel, and accommodations for scientific conferences: Accord, Merck, and Janssen. A.M. reports honoraria for speakerships from Bayer, Novartis, Daiichi Sankyo; and support for attending meetings and/or travel from Novartis. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 2018;359:1350-5. [Crossref] [PubMed]
2. Bimbatti D, Maruzzo M, Pierantoni F, et al. Immune checkpoint inhibitors rechallenge in urological tumors: An extensive review of the literature. Crit Rev Oncol Hematol 2022;170:103579. [Crossref] [PubMed]
3. Bajorin DF, Witjes JA, Gschwend JE, et al. Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. N Engl J Med 2021;384:2102-14. [Crossref] [PubMed]
4. Choueiri TK, Tomczak P, Park SH, et al. Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma. N Engl J Med 2021;385:683-94. [Crossref] [PubMed]
5. Necchi A, Faltas BM, Slovin SF, et al. Immunotherapy in the Treatment of Localized Genitourinary Cancers. JAMA Oncol 2023;9:1447-54. [Crossref] [PubMed]
6. Carthon BC, Wolchok JD, Yuan J, et al. Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin Cancer Res 2010;16:2861-71. [Crossref] [PubMed]
7. Lan T, Ran S, Gao M, et al. A narrative review of management of muscle-invasive bladder cancer perioperative period: will continuous and combined treatment be the new trend?. Transl Androl Urol 2024;13:293-307. [Crossref] [PubMed]
8. Wang S, Qi X, Liu D, et al. The implications for urological malignancies of non-coding RNAs in the the tumor microenvironment. Comput Struct Biotechnol J 2023;23:491-505. [Crossref] [PubMed]
9. Powles T, Eder JP, Fine GD, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature 2014;515:558-62. [Crossref] [PubMed]
10. Suartz CV, de Limac RD. Neoadjuvant Immunotherapy in Bladder Cancer: Ushering in a New Era of Treatment—A Systematic Review of Current Evidence. Eur Urol Open Sci 2025;79:45-59. [Crossref] [PubMed]
11. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409-13. [Crossref] [PubMed]
12. Goodman AM, Kato S, Bazhenova L, et al. Tumor Mutational Burden as an Independent Predictor of Response to Immunotherapy in Diverse Cancers. Mol Cancer Ther 2017;16:2598-608. [Crossref] [PubMed]
13. Michot JM, Bigenwald C, Champiat S, et al. Immune-related adverse events with immune checkpoint blockade: a comprehensive review. Eur J Cancer 2016;54:139-48. [Crossref] [PubMed]
14. Martins F, Sofiya L, Sykiotis GP, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol 2019;16:563-80. [Crossref] [PubMed]
15. Postow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N Engl J Med 2018;378:158-68. [Crossref] [PubMed]
16. Wu Z, Chen Q, Qu L, et al. Adverse Events of Immune Checkpoint Inhibitors Therapy for Urologic Cancer Patients in Clinical Trials: A Collaborative Systematic Review and Meta-analysis. Eur Urol 2022;81:414-25. [Crossref] [PubMed]
17. Bellmunt J, Powles T, Vogelzang NJ. A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: The future is now. Cancer Treat Rev 2017;54:58-67. [Crossref] [PubMed]
18. Galsky MD, Witjes JA, Gschwend JE, et al. Adjuvant Nivolumab in High-Risk Muscle-Invasive Urothelial Carcinoma: Expanded Efficacy From CheckMate 274. J Clin Oncol 2025;43:15-21. [Crossref] [PubMed]
19. Tannir NM, Albigès L, McDermott DF, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 8-year follow-up results of efficacy and safety from the phase III CheckMate 214 trial. Ann Oncol 2024;35:1026-38. [Crossref] [PubMed]
20. Powles T, Young A, Nimeiri H, et al. Molecular residual disease detection in resected, muscle-invasive urothelial cancer with a tissue-based comprehensive genomic profiling-informed personalized monitoring assay. Front Oncol 2023;13:1221718. [Crossref] [PubMed]
21. Bellmunt J, Hussain M, Gschwend JE, et al. Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol 2021;22:525-37. [Crossref] [PubMed]
22. Powles T, Assaf ZJ, Davarpanah N, et al. ctDNA guiding adjuvant immunotherapy in urothelial carcinoma. Nature 2021;595:432-7. [Crossref] [PubMed]
23. Apolo AB, Ballman KV, Sonpavde G, et al. Adjuvant Pembrolizumab versus Observation in Muscle-Invasive Urothelial Carcinoma. N Engl J Med 2025;392:45-55. [Crossref] [PubMed]
24. Rosenberg JE, Hoffman-Censits J, Powles T, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet 2016;387:1909-20. [Crossref] [PubMed]
25. Powles T, Catto JW, Galsky MD, et al. Perioperative durvalumab with neoadjuvant chemotherapy in operable bladder cancer. N Engl J Med 2024;391:1773-86. [Crossref] [PubMed]
26. Choueiri TK, Tomczak P, Park SH, et al. Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma. N Engl J Med 2024;390:1359-71. [Crossref] [PubMed]
27. Luke JJ, Long GV, Robert C, et al. Safety of pembrolizumab as adjuvant therapy in a pooled analysis of phase 3 clinical trials of melanoma, non-small cell lung cancer, and renal cell carcinoma. Eur J Cancer 2024;207:114146. [Crossref] [PubMed]
28. McDermott DF, Huseni MA, Atkins MB, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med 2018;24:749-57. Erratum in: Nat Med 2018;24:1941. [Crossref] [PubMed]
29. Antonarakis ES, Piulats JM, Gross-Goupil M, et al. Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study. J Clin Oncol 2020;38:395-405. [Crossref] [PubMed]
30. Taghizadeh H, Fajkovic H. Immunotherapy in the Management of Penile Cancer-A Systematic Review. Cancers (Basel) 2025;17:883. [Crossref] [PubMed]
31. Sharma P, Allison JP. The future of immune checkpoint therapy. Science 2015;348:56-61. [Crossref] [PubMed]
32. Haanen JBAG, Carbonnel F, Robert C, et al. Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2017;28:iv119-42. Erratum in: Ann Oncol 2018;29:iv264-6. [Crossref] [PubMed]
33. Gandara DR, Paul SM, Kowanetz M, et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med 2018;24:1441-8. [Crossref] [PubMed]
34. Basch E, Geoghegan C, Coons SJ, et al. Patient-Reported Outcomes in Cancer Drug Development and US Regulatory Review: Perspectives From Industry, the Food and Drug Administration, and the Patient. JAMA Oncol 2015;1:375-9. [Crossref] [PubMed]
35. Hellmann MD, Nathanson T, Rizvi H, et al. Genomic Features of Response to Combination Immunotherapy in Patients with Advanced Non-Small-Cell Lung Cancer. Cancer Cell 2018;33:843-52.e4. [Crossref] [PubMed]
36. Ding H, Xin W, Tong Y, et al. Cost effectiveness of immune checkpoint inhibitors for treatment of non-small cell lung cancer: A systematic review. PLoS One 2020;15:e0238536. [Crossref] [PubMed]