KEYNOTE-676: Phase III study of BCG and pembrolizumab for persistent/recurrent high-risk NMIBC

Kamat, Ashish M.; Shore, Neal D.; Hahn, Noah M.; Alanee, Shaheen; Nishiyama, Hiroyuki; Shariat, Shahrokh F.; Nam, Kijoeng; Kapadia, Ekta; Frenkl, Tara L.; Steinberg, Gary D.

doi:10.2217/fon-2019-0817

Cited by 58 publications

(33 citation statements)

References 47 publications

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“…This could be probably due to established immunosuppression in late stages that is beyond inversion or due to specific subtype related responses to immunotherapy as recently highlighted in a suggested classification system [ 80 ]. Despite the lack of a stratification method with high molecular precision in the clinic, anti-PD1 therapy is being tested in clinical trials to prevent recurrence and progression of high-risk NMIBC after tumor resection, as well as in conjunction with BCG therapy in a pre-surgical setting [ 81 ]. Recently, the FDA approved the use of anti-PD1 for BCG-unresponsive, high-risk NMIBC, after the therapy achieved responses in almost a third of patients [ 5 ].…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNAseq and longitudinal proteomic analysis of a novel semi-spontaneous urothelial cancer model reveals tumor cell heterogeneity and pretumoral urine protein alterations

et al. 2021

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Bladder cancer, one of the most prevalent malignancies worldwide, remains hard to classify due to a staggering molecular complexity. Despite a plethora of diagnostic tools and therapies, it is hard to outline the key steps leading up to the transition from high-risk non–muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC). Carcinogen-induced murine models can recapitulate urothelial carcinogenesis and natural anti-tumor immunity. Herein, we have developed and profiled a novel model of progressive NMIBC based on 10 weeks of OH-BBN exposure in hepatocyte growth factor/cyclin dependent kinase 4 (R24C) (Hgf-Cdk4R24C) mice. The profiling of the model was performed by histology grading, single cell transcriptomic and proteomic analysis, while the derivation of a tumorigenic cell line was validated and used to assess in vivo anti-tumor effects in response to immunotherapy. Established NMIBC was present in females at 10 weeks post OH-BBN exposure while neoplasia was not as advanced in male mice, however all mice progressed to MIBC. Single cell RNA sequencing analysis revealed an intratumoral heterogeneity also described in the human disease trajectory. Moreover, although immune activation biomarkers were elevated in urine during carcinogen exposure, anti-programmed cell death protein 1 (anti-PD1) monotherapy did not prevent tumor progression. Furthermore, anti-PD1 immunotherapy did not control the growth of subcutaneous tumors formed by the newly derived urothelial cancer cell line. However, treatment with CpG-oligodeoxynucleotides (ODN) significantly decreased tumor volume, but only in females. In conclusion, the molecular map of this novel preclinical model of bladder cancer provides an opportunity to further investigate pharmacological therapies ahead with regards to both targeted drugs and immunotherapies to improve the strategies of how we should tackle the heterogeneous tumor microenvironment in urothelial bladder cancer to improve responses rates in the clinic.

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Section: Discussionmentioning

confidence: 99%

Single-cell RNAseq and longitudinal proteomic analysis of a novel semi-spontaneous urothelial cancer model reveals tumor cell heterogeneity and pretumoral urine protein alterations

et al. 2021

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“…Several additional indications without biomarker requirements were approved over the past 5 years, including indications for the treatment of adult and pediatric patients with refractory classical Hodgkin's lymphoma (38,39), locally advanced or metastatic urothelial carcinoma for patients who are not eligible for cisplatin-containing chemotherapy or who have had disease progression during or following platinumcontaining chemotherapy (40,41), mediastinal large B cell lymphoma (42,43), hepatocellular carcinoma (44), Merkel cell carcinoma (45,46), patients with advanced renal cell carcinoma, recurrent or metastatic cutaneous squamous cell carcinoma (22,47), and patients with Bacillus Calmette-Guerin unresponsive, high-risk, non-muscle invasive bladder cancer (48).…”

Section: Pembrolizumab (Keytruda)mentioning

confidence: 99%

Cancer Immunotherapy Update: FDA-Approved Checkpoint Inhibitors and Companion Diagnostics

Twomey

Zhang

2021

AAPS J

436

299

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Immune checkpoint inhibitors (ICIs) are considered a new standard-of-care across many cancer indications. This review provides an update on ICIs approved by the Food and Drug Administration (FDA), with focus on monoclonal antibodies that target the programmed cell death 1 (PD-1) or its ligand, PD-1 ligand 1 (PD-L1), including information on their clinical indications and associated companion diagnostics. The information is further discussed with strategies for identifying predictive biomarkers to guide the clinical use of PD-1/PD-L1-targeted therapies.

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“…Several clinical trials with other ICI agents, both as monotherapy and as part of a combination therapy, are ongoing and in early-stage BC. Particularly relevant are the POTOMAC trial assessing durvalumab plus BCG in BCG-naïve patients, the KEYNOTE-676 study evaluating BCG-associated pembrolizumab in patients with recurrence after induction BCG therapy alone [33], and the NCT03317158 trial establishing the safety of durvalumab as monotherapy and in combination with BCG and external beam radiation therapy (EBRT) in BCG-unresponsive NMIBC patients (Table 2).…”

Section: Non-muscle Invasive Bladder Cancer (Nmibc)mentioning

confidence: 99%

Immune Checkpoint Inhibitors in Urothelial Bladder Cancer: State of the Art and Future Perspectives

Roviello

Catalano

Santi

et al. 2021

Cancers

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Bladder cancer (BC) is the most common malignancy of the genitourinary tract, with high morbidity and mortality rates. Until recently, the treatment of locally advanced or metastatic urothelial BC was based on the use of chemotherapy alone. Since 2016, five immune checkpoint inhibitors (ICIs) have been approved by the Food and Drug Administration (FDA) in different settings, i.e., first-line, maintenance and second-line treatment, while several trials are still ongoing in the perioperative context. Lately, pembrolizumab, a programmed death-1 (PD-1) inhibitor, has been approved for Bacillus Calmette–Guérin (BCG)-unresponsive high-risk non-muscle invasive bladder cancer (NMIBC), using immunotherapy at an early stage of the disease. This review investigates the current state and future perspectives of immunotherapy in BC, focusing on the rationale and results of combining immunotherapy with other therapeutic strategies.

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KEYNOTE-676: Phase III study of BCG and pembrolizumab for persistent/recurrent high-risk NMIBC

Cited by 58 publications

References 47 publications

Single-cell RNAseq and longitudinal proteomic analysis of a novel semi-spontaneous urothelial cancer model reveals tumor cell heterogeneity and pretumoral urine protein alterations

Single-cell RNAseq and longitudinal proteomic analysis of a novel semi-spontaneous urothelial cancer model reveals tumor cell heterogeneity and pretumoral urine protein alterations

Cancer Immunotherapy Update: FDA-Approved Checkpoint Inhibitors and Companion Diagnostics

Immune Checkpoint Inhibitors in Urothelial Bladder Cancer: State of the Art and Future Perspectives

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