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

Rosenberg, Jonathan E.; Hoffman-Censits, Jean H.; Powles, Tom; Heijden, Michiel S. van der; Balar, Arjun Vasant; Necchi, Andrea; Dawson, Nancy A.; O’Donnell, Peter H.; Balmanoukian, Ani Sarkis; Loriot, Yohann; Srinivas, Sandy; Retz, Margitta; Grivas, Petros; Joseph, Richard W.; Galsky, Matthew D.; Fleming, Mark T.; Petrylak, Daniel P.; Perez-Gracia, José Luis; Burris, Howard A.; Castellano, Daniel; Canil, Christina; Bellmunt, Joaquim; Bajorin, Dean F.; Nickles, Dorothee; Bourgon, Richard; Frampton, Garrett M.; Cui, Na; Mariathasan, Sanjeev; Abidoye, Oyewale O.; Fine, Gregg; Dreicer, Robert

doi:10.1016/s0140-6736(16)00561-4

Cited by 3,229 publications

(3,036 citation statements)

References 56 publications

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“…9,10,30–32 Although associated with efficacy, TMB has not yet been deemed sufficiently predictive to be of clinical use. Many tumors with high TMB are not responsive to immune checkpoint inhibitors.…”

Section: Discussionmentioning

confidence: 99%

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

et al. 2018

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Mounting evidence supports a role for the immune system in breast cancer outcomes. The ability to distinguish highly immunogenic tumors susceptible to anti-tumor immunity from weakly immunogenic or inherently immune-resistant tumors would guide development of therapeutic strategies in breast cancer. Genomic, transcriptomic and clinical data from The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) breast cancer cohorts were used to examine statistical associations between tumor mutational burden (TMB) and the survival of patients whose tumors were assigned to previously-described prognostic immune subclasses reflecting favorable, weak or poor immune-infiltrate dispositions (FID, WID or PID, respectively). Tumor immune subclasses were associated with survival in patients with high TMB (TMB-Hi, P < 0.001) but not in those with low TMB (TMB-Lo, P = 0.44). This statistical relationship was confirmed in the METABRIC cohort (TMB-Hi, P = 0.047; TMB-Lo, P = 0.39), and also found to hold true in the more-indolent Luminal A tumor subtype (TMB-Hi, P = 0.011; TMB-Lo, P = 0.91). In TMB-Hi tumors, the FID subclass was associated with prolonged survival independent of tumor stage, molecular subtype, age and treatment. Copy number analysis revealed the reproducible, preferential amplification of chromosome 1q immune-regulatory genes in the PID immune subclass. These findings demonstrate a previously unappreciated role for TMB as a determinant of immune-mediated survival of breast cancer patients and identify candidate immune-regulatory mechanisms associated with immunologically cold tumors. Immune subtyping of breast cancers may offer opportunities for therapeutic stratification.

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Section: Discussionmentioning

confidence: 99%

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

et al. 2018

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“…19 Previous clinical data indicate that an improved ORR to atezolizumab amongst urothelial carcinoma patients is associated with >5% positive staining for PD-L1 (as assessed by the SP142 assay) on tumor-infiltrating immune cells. 10 , 18 Conversely, PD-L1 positivity by neoplastic or immune cells (as assessed by the 22C3 assay) reportedly fails to correlate with improved objective responses to pembrolizumab in urothelial carcinoma patients. 7 This patient exhibited a durable disease stabilization on pembrolizumab (associated with an increase in survival as compared to expectations) despite no PD-L1 positivity in tumor-infiltrating immune cells and no membranous PD-L1 expression by malignant cells.…”

Section: Discussionmentioning

confidence: 99%

“…15-17 Specifically, the IMvigor 210 trial (NCT02108652) demonstrated that urothelial carcinoma patients treated with atezolizumab exhibit an increased objective response rate (ORR) when their lesions stain positively (>5% of cells) for PD-L1. 10 , 18 Nonetheless, ORR never exceeded 26%, even amongst patients with the highest IHC score for PD-L1 expression. 10 , 18 In the same setting, whole-exon DNA-seq on a subset of patients demonstrated an increased likelihood for response amongst subjects with high MuB, although a considerable overlap existed between this group and individuals with low MuB.…”

Section: Introductionmentioning

confidence: 91%

“…10 , 18 Nonetheless, ORR never exceeded 26%, even amongst patients with the highest IHC score for PD-L1 expression. 10 , 18 In the same setting, whole-exon DNA-seq on a subset of patients demonstrated an increased likelihood for response amongst subjects with high MuB, although a considerable overlap existed between this group and individuals with low MuB. 10 , 18 These findings led to the development of IHC-based companion diagnostics for the detection of PD-L1 expression levels in tumor biopsies, including the SP142 assay 19 from Ventana Medical Systems (Tucson, AZ, USA) and the 22C3 assay 20 from Dako Inc. (Santa Clara, CA, USA).…”

Section: Introductionmentioning

confidence: 91%

“…10 , 18 In the same setting, whole-exon DNA-seq on a subset of patients demonstrated an increased likelihood for response amongst subjects with high MuB, although a considerable overlap existed between this group and individuals with low MuB. 10 , 18 These findings led to the development of IHC-based companion diagnostics for the detection of PD-L1 expression levels in tumor biopsies, including the SP142 assay 19 from Ventana Medical Systems (Tucson, AZ, USA) and the 22C3 assay 20 from Dako Inc. (Santa Clara, CA, USA). Neither of these assays, however, is currently approved by the US FDA as a companion diagnostic for predicting responses to ICBs amongst urothelial carcinoma patients (22C3 is approved for predicting responses to pembrolizumab amongst non-small cell lung carcinoma and gastroesophageal carcinoma patients; source https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm301431.htm).…”

Section: Introductionmentioning

confidence: 99%

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PD-L2 amplification and durable disease stabilization in patient with urothelial carcinoma receiving pembrolizumab

George

Papanicolau‐Sengos²,

Lenzo³

et al. 2018

OncoImmunology

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We report the immunological profile of a patient with upper-tract urothelial carcinoma experiencing stable disease on pembrolizumab for 20 months. The tumor exhibited extensive infiltration by CD8+ cytotoxic T lymphocytes, low-to-moderate mutational burden, no PD-L1 staining by commercially available immunohistochemical assays, but amplification of CD274 (coding for PD-L1) and/or PDCD1LG2 (encoding PD-L2) by fluorescence in situ hybridization. RNA-seq revealed multiple biomarkers of an ongoing immune response and compensatory immune evasion, including moderate PD-L1 levels coupled with robust PD-L2 expression. Pending validation in additional patients, these findings suggest that PD-L2 expression levels may constitute a biomarker of response to immune checkpoint blockade in urothelial carcinoma.

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Significance of PD-L1 in Metastatic Urothelial Carcinoma Treated With Immune Checkpoint Inhibitors

Maiorano,

Di Maio,

Cerbone

et al. 2024

JAMA Netw Open

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ImportanceImmune checkpoint inhibitors (ICIs) have broadened the metastatic urothelial carcinoma (mUC) therapeutic scenario. The association of programmed death ligand 1 (PD-L1) with response and survival in patients treated with ICIs is still controversial.ObjectivesTo evaluate the association of PD-L1 with response rate and overall survival among patients with mUC treated with ICIs.Data SourcesPubMed, Embase, American Society of Clinical Oncology and European Society for Medical Oncology Meeting Libraries, and Web of Science were searched up to December 10, 2023.Study SelectionTwo authors independently screened the studies. Included studies were randomized and nonrandomized clinical trials enrolling patients with mUC receiving ICIs with available overall survival (OS), progression-free survival (PFS), or overall response rate (ORR) data, separated between patients with PD-L1–positive and –negative tumors.Data Extraction and SynthesisThe Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Two reviewers independently extracted data. Fixed- or random-effects models were used depending on the heterogeneity among the studies.Main Outcomes and MeasuresPrimary outcomes were odds ratios (ORs) for ORR and hazard ratios (HRs) for OS, comparing patients with PD-L1–positive tumors and patients with PD-L1–negative tumors. Secondary outcomes were the PFS HR between patients with PD-L1–positive and –negative tumors and OS HR between ICI arms and non-ICI arms of only randomized clinical trials.ResultsA total of 14 studies were selected, comprising 5271 patients treated with ICIs (2625 patients had PD-L1–positive tumors). The ORR was 13.8% to 78.6% in patients with PD-L1–positive tumors and 5.1% to 63.2% in patients with PD-L1–negative tumors, with an association between PD-L1 status and ORR favoring patients with PD-L1–positive tumors (OR, 1.94; 95% CI, 1.47-2.56; P &lt; .001). Median OS ranged from 8.4 to 24.1 months in patients with PD-L1–positive tumors and from 6.0 to 19.1 months in patients with PD-L1–negative tumors. The pooled HR showed a significant reduction for patients with PD-L1–positive tumors compared with those with PD-L1–negative tumors in the risk of death (HR, 0.71; 95% CI, 0.57-0.89; P = .003) and risk of progression (HR, 0.55; 95% CI, 0.44-0.69; P &lt; .001) when ICIs were administered. PD-L1 is not likely to be a predictive biomarker of ICI response.Conclusions and RelevanceThis systematic review and meta-analysis suggests that PD-L1 expression is associated with improved ORR, OS, and PFS for patients with mUC who receive ICIs, but it is unlikely to be useful as a predictive biomarker. Developing predictive biomarkers is essential to select patients most likely to benefit from ICIs and avoid toxic effects and financial burden with these agents.

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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

Cited by 3,229 publications

References 56 publications

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

Tumor mutational burden is a determinant of immune-mediated survival in breast cancer

PD-L2 amplification and durable disease stabilization in patient with urothelial carcinoma receiving pembrolizumab

Significance of PD-L1 in Metastatic Urothelial Carcinoma Treated With Immune Checkpoint Inhibitors

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