Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study

Balar, Arjun Vasant; Kamat, Ashish M.; Kulkarni, Girish S.; Uchio, Edward; Boormans, Joost L.; Roumiguié, M.; Krieger, Laurence E.; Singer, Eric A.; Bajorin, Dean F.; Grivas, Petros; Seo, Ho Kyung; Nishiyama, Hiroyuki; Konety, Badrinath R.; Li, Haojie; Nam, Kijoeng; Kapadia, Ekta; Frenkl, Tara L.; Wit, Ronald de

doi:10.1016/s1470-2045(21)00147-9

Cited by 267 publications

(137 citation statements)

References 22 publications

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“…Despite recent advances in OC treatment, most OC patients diagnosed at advanced stages and have poor prognoses, with a recurrence rate of 70% within 3 years and only 30% 5-year survival rate (2,3). Immunotherapy is a promising treatment strategy for many cancers, and immunotherapy has led to improved quality of life and prolonged survival for some OC patients (4)(5)(6). However, immunotherapy for ovarian cancer still faces challenges, with only 8-9% objective response and a lack of reliable biomarkers to predict response (7).…”

Section: Introductionmentioning

confidence: 99%

Multi-Omics Profiling Identifies Risk Hypoxia-Related Signatures for Ovarian Cancer Prognosis

Chen

Lan

et al. 2021

Front. Immunol.

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BackgroundOvarian cancer (OC) has the highest mortality rate among gynecologic malignancy. Hypoxia is a driver of the malignant progression in OC, which results in poor prognosis. We herein aimed to develop a validated model that was based on the hypoxia genes to systematically evaluate its prognosis in tumor immune microenvironment (TIM).ResultsWe identified 395 hypoxia-immune genes using weighted gene co-expression network analysis (WGCNA). We then established a nine hypoxia-related genes risk model using least absolute shrinkage and selection operator (LASSO) Cox regression, which efficiently distinguished high-risk patients from low-risk ones. We found that high-risk patients were significantly related to poor prognosis. The high-risk group showed unique immunosuppressive microenvironment, lower antigen presentation, and higher levels of inhibitory cytokines. There were also significant differences in somatic copy number alterations (SCNAs) and mutations between the high- and low-risk groups, indicating immune escape in the high-risk group. Tumor immune dysfunction and exclusion (TIDE) and SubMap algorithms showed that low-risk patients are significantly responsive to programmed cell death protein-1 (PD-1) inhibitors.ConclusionsIn this study, we highlighted the clinical significance of hypoxia in OC and established a hypoxia-related model for predicting prognosis and providing potential immunotherapy strategies.

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Section: Introductionmentioning

confidence: 99%

Multi-Omics Profiling Identifies Risk Hypoxia-Related Signatures for Ovarian Cancer Prognosis

Chen

Lan

et al. 2021

Front. Immunol.

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“…In 13 patients (13%), grade 3 or 4 adverse events related to the treatment occurred, with hyponatremia and arthralgia being the most frequent (3% and 2% of cases, respectively). In 8% of patients, treatment-related adverse events were serious, but no deaths were recorded [52].…”

Section: Bgg-unresponsive Nmibtmentioning

confidence: 98%

“…There is a paucity of data of treatment with PD-L1 inhibitors in high-risk NMIBC patients. In the single-arm phase 2 KEYNOTE-057 study [52], the effect of pembrolizumab was evaluated in patients with high-risk BCG-unresponsive NMIBC who declined to undergo or were ineligible for cystectomy and were treated with pembrolizumab 200 mg every 3 weeks for 24 months or until recurrence, progression, or unacceptable toxicity. Results were updated (median follow-up 36.4, range 32.0-40.7) and, at 3 months, in the group of 96 patients with carcinoma in situ unresponsive to BCG, with or without papillary tumors, 41% (n = 39) showed a complete response.…”

Section: Bgg-unresponsive Nmibtmentioning

confidence: 99%

Recent Advances in the Management of Patients with Non-Muscle-Invasive Bladder Cancer Using a Multidisciplinary Approach: Practical Recommendations from the Spanish Oncology Genitourinary (SOGUG) Working Group

Rubio‐Briones

Algaba

Gallardo

et al. 2021

Cancers

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On the basis of the discussion of the current state of research on relevant topics of non-muscle-invasive bladder cancer (NMIBC) among a group of experts of the Spanish Oncology Genitourinary (SOGUG) Working Group, recommendations were proposed to overcome the challenges posed by the management of NMIBC in clinical practice. A unified definition of the term ‘microhematuria’ and the profile of the patient at risk are needed. Establishing a ‘hematuria clinic’ would contribute to a centralized and more efficient evaluation of patients with this clinical sign. Second or repeated transurethral resection (re-TUR) needs to be defined, including the time window after the first procedure within which re-TUR should be performed. Complete tumor resection is mandatory when feasible, with specification of the presence or absence of muscle. Budding should be used as a classification system, and stratification of T1 tumors especially in extensive and deep tumors, is advisable. The percentage of the high-grade component should always be reported, and, in multiple tumors, grades should be reported separately. Luminal and basal subtypes can be identified because of possibly different clinical outcomes. Molecular subtypes and immunotherapy are incorporated in the management of muscle-invasive bladder cancer but data on NMIBC are still preliminary.

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“…Radical cystectomy was required in 37.5% of patients but up-staging to muscle-invasive bladder cancer was observed in less than 10% of patients. 32 Pembrolizumab is the first agent approved by the FDA for BCG-unresponsive NMIBC since valrubicin. It marks a key milestone in the development of novel therapeutics for this disease.…”

Section: Novel Therapies For Bcg-unresponsive High-risk Nmibcmentioning

confidence: 99%

Novel and emerging approaches in the management of non-muscle invasive urothelial carcinoma

2021

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Non-muscle invasive bladder cancer (NMIBC) has traditionally been managed with transurethral resection followed by intravesical chemotherapy and/or bacillus Calmette–Guerin (BCG) in a risk-adapted manner. These tumors commonly recur and can progress potentially to lethal muscle invasive disease. A major unmet need in the field of NMIBC is bladder preserving therapy for recurrent high-grade NMIBC after adequate intravesical BCG therapy. The current gold standard treatment for these BCG-unresponsive patients is radical cystectomy, which is associated with considerable morbidity and mortality, particularly in older and frailer patients. It is therefore critical to provide alternative treatment options with acceptable oncological outcomes. In this review we explore novel bladder-sparing treatment options including combination intravesical therapy, enhanced instillation methods, immunotherapy, gene therapy, targeted therapy, photodynamic therapy and BCG variants across the spectrum of NMIBC disease states, ranging from low grade BCG-naïve patients through to high-grade BCG-unresponsive NMIBC.

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Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study

Cited by 267 publications

References 22 publications

Multi-Omics Profiling Identifies Risk Hypoxia-Related Signatures for Ovarian Cancer Prognosis

Multi-Omics Profiling Identifies Risk Hypoxia-Related Signatures for Ovarian Cancer Prognosis

Recent Advances in the Management of Patients with Non-Muscle-Invasive Bladder Cancer Using a Multidisciplinary Approach: Practical Recommendations from the Spanish Oncology Genitourinary (SOGUG) Working Group

Novel and emerging approaches in the management of non-muscle invasive urothelial carcinoma

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