Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma

Bellmunt, Joaquim; Wit, Ronald de; Vaughn, David J.; Fradet, Yves; Lee, Jae‐Lyun; Fong, Lawrence; Vogelzang, Nicholas J.; Climent, Miguel Ángel; Petrylak, Daniel P.; Choueiri, Toni K.; Necchi, Andrea; Gerritsen, Winald R.; Gurney, Howard; Quinn, David I.; Culine, Stéphane; Sternberg, Cora N.; Mai, Yabing; Poehlein, Christian; Perini, Rodolfo F.; Bajorin, Dean F.

doi:10.1056/nejmoa1613683

Cited by 2,853 publications

(2,632 citation statements)

References 27 publications

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“…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: 64%

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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Section: Discussionmentioning

confidence: 64%

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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“…1–10 Given the ubiquitous use of corticosteroids in the medical management of cancer patients and their immunosuppressive effects, this study primarily sought to determine whether responses mediated by anti-PD-1 therapy are influenced by corticosteroids in a preclinical setting. Utilizing well-established in vivo tumor models that are sensitive to PD-1 blockade, this study examined whether dexamethasone’s impact was dependent on its timing, duration, and tumor location within or outside the CNS.…”

Section: Discussionmentioning

confidence: 99%

“…1–10 As the list of approvals and clinical trials investigating its efficacy in other tumor types continues to grow, it is paramount to determine factors, both tumor-intrinsic and extrinsic, that influence responses to anti-PD-1 therapy. 11 An important concern to address is how iatrogenic immunosuppression caused by conventional therapies such as chemotherapy, fractionated radiotherapy, and corticosteroids may potentially impact the efficacy of anti-PD-1 as well as other immunotherapy strategies.…”

Section: Introductionmentioning

confidence: 99%

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

et al. 2018

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Immune checkpoint blockade targeting programmed cell death protein 1 (PD-1) is emerging as an important treatment strategy in a growing list of cancers, yet its clinical benefits are limited to a subset of patients. Further investigation of tumor-intrinsic predictors of response and how extrinsic factors, such as iatrogenic immunosuppression caused by conventional therapies, impact the efficacy of anti-PD-1 therapy are paramount. Given the widespread use of corticosteroids in cancer management and their immunosuppressive nature, this study sought to determine how corticosteroids influence anti-PD-1 responses and whether their effects were dependent on tumor location within the periphery versus central nervous system (CNS), which may have a more limiting immune environment. In well-established anti-PD-1-responsive murine tumor models, corticosteroid therapy resulted in systemic immune effects, including severe and persistent reductions in peripheral CD4+ and CD8 + T cells. Corticosteroid treatment was found to diminish the efficacy of anti-PD-1 therapy in mice bearing peripheral tumors with responses correlating with peripheral CD8/Treg ratio changes. In contrast, in mice bearing intracranial tumors, corticosteroids did not abrogate the benefits conferred by anti-PD-1 therapy. Despite systemic immune changes, anti-PD-1-mediated antitumor immune responses remained intact during corticosteroid treatment in mice bearing intracranial tumors. These findings suggest that anti-PD-1 responses may be differentially impacted by concomitant corticosteroid use depending on tumor location within or outside the CNS. As an immune-specialized site, the CNS may potentially play a protective role against the immunosuppressive effects of corticosteroids, thus sustaining antitumor immune responses mediated by PD-1 blockade.

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“…12,13 ). However, even among such potentially immunogenic cancers, immune checkpoint inhibitors benefit only a relatively small number of patients 7,12,14–18 . As resistance may be due to the activation of alternative checkpoint pathways, additional immune checkpoints targets have become a subject of active research, including the T-cell Immunoglobulin and Mucin-domain- containing molecule 3 (TIM-3) 19 .…”

Section: Introductionmentioning

confidence: 99%

TIM-3 expression in breast cancer

et al. 2018

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Tumor-infiltrating lymphocytes (TILs) are predominantly present in breast cancer patients with estrogen receptor negative tumors, among whom increasing levels correlate with favorable outcomes. Nevertheless, currently available immune checkpoint inhibitors appear to benefit only a small number of women with breast cancer. Upregulation of additional immune checkpoint markers is one mechanism of resistance to current inhibitors that might be amenable to targeting with newer agents. T-cell Immunoglobulin and Mucin domain-containing molecule 3 (TIM-3) is an immune checkpoint receptor that is an emerging target for cancer immunotherapy. We investigated TIM-3 immunohistochemical expression in 3,992 breast cancer specimens assembled into tissue microarrays, linked to detailed outcome, clinico-pathological parameters and biomarkers including CD8, PD-1, PD-L1 and LAG-3. We scored and reported absolute counts for TIM-3+ intra-epithelial and stromal TILs (iTILs and sTILs), and find that breast cancer patients with TIM-3+ iTILs (≥ 1) represent a minority of cases (11%), with a predilection for basal-like breast cancers (among which 28% had TIM-3+ iTILs). TIM-3+ sTILs (≥ 2) represented 20% of cases and included more non-basal cases. The presence of TIM-3+ iTILs highly correlates with hematoxylin and eosin-stained stromal TILs and with other immune checkpoint markers (PD-1+ iTILs, LAG-3+ iTILs and PD-L1+ tumors). In prognostic analyses, early breast cancer patients with TIM-3+ iTILs have significantly improved breast cancer-specific survival whereas TIM-3+ sTILs did not reach statistical significance. In multivariate analyses, the presence of TIM-3+ iTILs is an independent favorable prognostic factor in the whole cohort as well as among ER negative patients. Our study supports TIM-3 as a target for breast cancer immunotherapy.

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Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma

Abstract: BACKGROUND-Patients with advanced urothelial carcinoma that progresses after platinumbased chemotherapy have a poor prognosis and limited treatment options.

Cited by 2,853 publications

References 27 publications

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

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

Contrasting impact of corticosteroids on anti-PD-1 immunotherapy efficacy for tumor histologies located within or outside the central nervous system

TIM-3 expression in breast cancer

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