Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial

Bellmunt, Joaquim; Hussain, Maha; Gschwend, Jürgen E.; Albers, Peter; Oudard, Stéphane; Castellano, Daniel; Daneshmand, Siamak; Nishiyama, Hiroyuki; Majchrowicz, Martin; Degaonkar, Viraj; Shi, Yi; Mariathasan, Sanjeev; Grivas, Petros; Drakaki, Alexandra; O’Donnell, Peter H.; Rosenberg, Jonathan E.; Geynisman, Daniel M.; Petrylak, Daniel P.; Hoffman-Censits, Jean H.; Bedke, Jens; Kalebasty, Arash Rezazadeh; Zakharia, Yousef; Heijden, Michiel S. van der; Sternberg, Cora N.; Davarpanah, Nicole N.; Schmid, Peter

doi:10.1016/s1470-2045(21)00004-8

Cited by 289 publications

(253 citation statements)

References 30 publications

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“…Moreover, our present data are strongly supported by recent results from IMvigor010, where atezolizumab failed to prolong patient outcomes when administered as adjuvant maintenance therapy after radical cystectomy. Although not analyzed in detail, the authors reported that high PD-L1 expression on IC (IC ≥ 5%) indicated favorable post-cystectomy outcomes but was not able to predict benefits of adjuvant atezolizumab treatment [ 32 ]. In contrast, preliminary results from Checkmate274 showed that adjuvant nivolumab treatment following radical surgery prolongs disease-free survival partially dependent on PD-L1 expression on TC (NCT02632409).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, these immune cell phenotypes cannot be resolved properly using current PD-L1 algorithms. Thus, questions have to be raised, such as which patients benefit from immunotherapy or only have a minor benefit, since treatment can also be accompanied by relatively strong adverse side effects, as reported in adjuvant therapy settings [ 32 ]. For example, patients with a strong anti-tumor immune response and favorable baseline outcomes might benefit from immune therapy by further unleashing the immune response in the MIBC TIME.…”

Section: Discussionmentioning

confidence: 99%

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Integration of Spatial PD-L1 Expression with the Tumor Immune Microenvironment Outperforms Standard PD-L1 Scoring in Outcome Prediction of Urothelial Cancer Patients

Weyerer

Strissel

Strick

et al. 2021

Cancers

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Background: Immune therapy has gained significant importance in managing urothelial cancer. The value of PD-L1 remains a matter of controversy, thus requiring an in-depth analysis of its biological and clinical relevance. Methods: A total of 193 tumors of muscle-invasive bladder cancer patients (MIBC) were assessed with four PD-L1 assays. PD-L1 scoring results were correlated with data from a comprehensive digital-spatial immune-profiling panel using descriptive statistics, hierarchical clustering and uni-/multivariable survival analyses. Results: PD-L1 scoring algorithms are heterogeneous (agreements from 63.1% to 87.7%), and stems from different constellations of immune and tumor cells (IC/TC). While Ventana IC5% algorithm identifies tumors with high inflammation and favorable baseline prognosis, CPS10 and the TCarea25%/ICarea25% algorithm identify tumors with TC and IC expression. Spatially organized immune phenotypes, which correlate either with high PD-L1 IC expression and favorable prognosis or constitutive PD-L1 TC expression and poor baseline prognosis, cannot be resolved properly by PD-L1 algorithms. PD-L1 negative tumors with relevant immune infiltration can be detected by sTILs scoring on HE slides and digital CD8+ scoring. Conclusions: Contemporary PD-L1 scoring algorithms are not sufficient to resolve spatially distributed MIBC immune phenotypes and their clinical implications. A more comprehensive view of immune phenotypes along with the integration of spatial PD-L1 expression on IC and TC is necessary in order to stratify patients for ICI.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Integration of Spatial PD-L1 Expression with the Tumor Immune Microenvironment Outperforms Standard PD-L1 Scoring in Outcome Prediction of Urothelial Cancer Patients

Weyerer

Strissel

Strick

et al. 2021

Cancers

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“…PD-L1 biomarkers were not useful in stratifying patients potentially benefiting from adjuvant treatment. A slightly higher difference in the rate of adverse events was observed between the two groups, with a 33% discontinuation rate in the atezolizumab arm [17]. CheckMate-274 has recently released preliminary results [18].…”

Section: 2mentioning

confidence: 98%

Adjuvant Systemic Therapy for High-risk Muscle-invasive Bladder Cancer After Radical Cystectomy: Current Options and Future Opportunities

Mir

Campi

Loriot

et al. 2022

European Urology Oncology

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We describe the case of a 71-yr-old woman with locally advanced muscle-invasive bladder cancer and stage III chronic kidney disease due to an obstructed nonfunctional left kidney. She was started on neoadjuvant immunotherapy, but had to stop treatment because of acute worsening of renal function. Radical cystectomy was then performed uneventfully, revealing pT3aN1 urothelial carcinoma of the bladder. Adjuvant chemotherapy in high-risk locally advanced bladder cancer after radical cystectomy currently poses several challenges, especially for cisplatinineligible candidates. Recent data on adjuvant immunotherapy trials suggest a disease-free survival advantage for this subgroup of patients. The current and future role of immuno-oncology agents in this setting is discussed. Patient summary: Patients with advanced bladder cancer might benefit from further chemotherapy or immunotherapy following bladder removal, but it is still unclear which patients benefit the most from this strategy. Measurement of biomarkers and scans to show urinary function will probably help in optimising patient selection for this treatment in the near future.

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“…The role of adjuvant immunotherapy in MIBC patients after cystectomy remains to be elucidated by prospective clinical studies. One phase III trial (IMvigor010) did not meet its primary endpoint of improved disease-free survival in the atezolizumab group over observation (19.4 vs 16.6 months; HR, 0.89 [95% CI, 0.74-1.08]; P = .24) ( 47 ). On the other hand, first results from the phase III CheckMate 274 trial supported use of nivolumab in MIBC after radical surgery ( 48 ).…”

Section: The Advances and Challenges Of Immunotherapy For Ubcmentioning

confidence: 99%

Immunotherapy in the Treatment of Urothelial Bladder Cancer: Insights From Single-Cell Analysis

Zang

Yang

et al. 2021

Front. Oncol.

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Urothelial bladder cancer (UBC) is a global challenge of public health with limited therapeutic options. Although the emergence of cancer immunotherapy, most notably immune checkpoint inhibitors, represents a major breakthrough in the past decade, many patients still suffer from unsatisfactory clinical outcome. A thorough understanding of the fundamental cellular and molecular mechanisms responsible for antitumor immunity may lead to optimized treatment guidelines and new immunotherapeutic strategies. With technological developments and protocol refinements, single-cell approaches have become powerful tools that provide unprecedented insights into the kaleidoscopic tumor microenvironment and intricate cell-cell communications. In this review, we summarize recent applications of single-cell analysis in characterizing the UBC multicellular ecosystem, and discuss how to leverage the high-resolution information for more effective immune-based therapies.

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Adjuvant atezolizumab versus observation in muscle-invasive urothelial carcinoma (IMvigor010): a multicentre, open-label, randomised, phase 3 trial

Cited by 289 publications

References 30 publications

Integration of Spatial PD-L1 Expression with the Tumor Immune Microenvironment Outperforms Standard PD-L1 Scoring in Outcome Prediction of Urothelial Cancer Patients

Integration of Spatial PD-L1 Expression with the Tumor Immune Microenvironment Outperforms Standard PD-L1 Scoring in Outcome Prediction of Urothelial Cancer Patients

Adjuvant Systemic Therapy for High-risk Muscle-invasive Bladder Cancer After Radical Cystectomy: Current Options and Future Opportunities

Immunotherapy in the Treatment of Urothelial Bladder Cancer: Insights From Single-Cell Analysis

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