Safety and Activity of Programmed Cell Death 1 Versus Programmed Cell Death Ligand 1 Inhibitors for Platinum-Resistant Urothelial Cancer: A Meta-Analysis of Published Clinical Trials

BackgroundProgrammed death 1/ligand 1 (PD-1/L1) inhibitors have acceptable antitumor activity in patients with platinum-resistant urothelial cancer (UC). However, the reliability and comparability of the antitumor activity, safety profiles and survival outcomes of different immune checkpoint inhibitors are unknown. Our objective was to compare the clinical efficacy and safety of anti–PD-1/PD-L1 therapies in platinum-resistant UC patients.MethodsWe reviewed the published trials from the PubMed, Embase and Cochrane Library databases up to August 2020. A well-designed mirror principle strategy to screen and pair trial characteristics was used to justify indirect comparisons. The primary end point was the objective response rate (ORR). The safety profile and survival outcomes were also evaluated. The restricted mean survival time (RMST) up to 12 months was calculated.ResultsEight studies including 1,666 advanced or metastatic UC patients (1,021 patients with anti–PD-L1 treatment and 645 patients with anti–PD-1 treatment) met the study criteria. The ORRs of anti–PD-1 and PD-L1 therapy were 22% (95% CI, 18%–25%) and 15% (95% CI, 13%–17%) with all studies combined. The proportions of the treated population with a confirmed objective response (I2 = 0; P = 0.966; HR, 1.60; 95% CI, 1.23–2.07; P < 0.001) and disease control (I2 = 30.6%; P = 0.229; HR, 1.35; 95% CI, 1.10–1.66; P = 0.004) were higher with anti–PD-1 therapy than with anti–PD-L1 therapy. The treatment-related adverse events (AEs) (I2 = 78.3%; P = 0.003; OR, 1.09; 95% CI, 0.65–1.84; P = 0.741) and grade 3–5 treatment-related AEs (I2 = 68.5%; P = 0.023; OR, 1.69; 95% CI, 0.95–3.01; P = 0.074) of anti–PD-1 therapy were comparable to those of anti–PD-L1 therapy. The RMST values at the 12-month follow-up were 9.4 months (95% CI,: 8.8–10.0) for anti–PD-1 therapy and 9.3 months (95% CI, 8.8–9.7) for anti–PD-L1 therapy (z = 0.26, P = 0.794). There was no significant difference between patients in the anti–PD-1 and anti–PD-L1 groups (12-month overall survival (OS): 43% versus 42%, P = 0.765. I2 = 0; P = 0.999; HR, 0.95; 95% CI, 0.83–1.09; P = 0.474).ConclusionsThe results of our systematic comparison suggest that anti–PD-1 therapy exhibits better antitumor activity than anti–PD-L1 therapy, with comparable safety profiles and survival outcomes. These findings may contribute to enhanced treatment awareness in patients with platinum-resistant UC.

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Expression of PD-L1 for predicting response to immune checkpoint inhibitors in metastatic urothelial carcinoma: a systematic review and meta-analysis

Current Oncology ◽

10.3747/co.27.6437 ◽

2020 ◽

Vol 27 (6) ◽

Author(s):

J. Huang ◽

X. Teng

Keyword(s):

Urothelial Cancer ◽

Checkpoint Inhibitors ◽

Meta Analysis ◽

Objective Response ◽

High Sensitivity ◽

Cochrane Library ◽

Significant Difference ◽

Metastatic Urothelial Carcinoma ◽

The Cochrane Library ◽

Expression Status

Background We conducted this meta-analysis and systematic literature review to study the ability of PD-L1 to predict objective response in patients with urothelial cancer treated with PD-1/PD-L1 inhibitors. Methods Relevant studies of PD-1 or PD-L1 inhibitors in urothelial cancer that reported objective response rate (orr) based on PD-L1 expression status in PubMed, embase, and the Cochrane Library were retrieved. Efficacy of PD-L1 expression status in predicting orr and the efficacy, safety of PD-1 and PD-L1 drugs were analyzed. Results Studies were divided into ≥1%, ≥5%, and ≥25% based on PD-L1 positivity threshold, and the patients were grouped into PD-L1 positive and negative. In all 3 expression thresholds, patients with positive PD-L1 expression were more likely to experience an objective response [≥1% threshold odds ratio (or): 1.74; 95% confidence interval (ci): 1.20 to 2.53; ≥5% threshold or: 2.74; 95% ci: 2.01 to 3.724; ≥25% threshold or: 7.13; 95% ci: 2.38 to 21.40] in comparison with patients with negative PD-L1 expression. Of the 3 thresholds, the ≥25% threshold was better in predicting orr (1.74 vs. 2.93 vs. 7.13; p < 0.0001). The ≥1% PD-L1 threshold had a relatively high sensitivity in predicting orr; the ≥5% PD-L1 threshold was better for specificity. Sensitivity was higher at the ≥25% threshold than at the other two thresholds, but specificity was lower. Further, we found that there is no statistically significant difference in efficacy between PD-1 and PD-L1 drugs. Conclusions Urothelial cancer patients with PD-L1 positive expression responded better than PD-L1 negative patients did, and a threshold of ≥5% or greater for PD-L1 expression might predict positive clinical response.

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Importance of the PD-1/PD-L1 Axis for Malignant Transformation and Risk Assessment of Oral Leukoplakia

Biomedicines ◽

10.3390/biomedicines9020194 ◽

2021 ◽

Vol 9 (2) ◽

pp. 194

Author(s):

Jutta Ries ◽

Abbas Agaimy ◽

Falk Wehrhan ◽

Christoph Baran ◽

Stella Bolze ◽

...

Keyword(s):

Immune Response ◽

Cell Death ◽

Programmed Cell Death ◽

Malignant Transformation ◽

Immune Escape ◽

Checkpoint Inhibitors ◽

Precancerous Lesions ◽

Death Receptor ◽

Oral Leukoplakia ◽

Significant Difference

Background: The programmed cell death ligand 1/programmed cell death receptor 1 (PD-L1/PD-1) Immune Checkpoint is an important modulator of the immune response. Overexpression of the receptor and its ligands is involved in immunosuppression and the failure of an immune response against tumor cells. PD-1/PD-L1 overexpression in oral squamous cell carcinoma (OSCC) compared to healthy oral mucosa (NOM) has already been demonstrated. However, little is known about its expression in oral precancerous lesions like oral leukoplakia (OLP). The aim of the study was to investigate whether an increased expression of PD-1/PD-L1 already exists in OLP and whether it is associated with malignant transformation. Material and Methods: PD-1 and PD-L1 expression was immunohistologically analyzed separately in the epithelium (E) and the subepithelium (S) of OLP that had undergone malignant transformation within 5 years (T-OLP), in OLP without malignant transformation (N-OLP), in corresponding OSCC and in NOM. Additionally, RT-qPCR analysis for PD-L1 expression was done in the entire tissues. Additionally, the association between overexpression and malignant transformation, dysplasia and inflammation were examined. Results: Compared to N-OLP, there were increased levels of PD-1 protein in the epithelial and subepithelial layers of T-OLP (pE = 0.001; pS = 0.005). There was no significant difference in PD-L1 mRNA expression between T-OLP and N-OLP (p = 0.128), but the fold-change increase between these groups was significant (Relative Quantification (RQ) = 3.1). In contrast to N-OLP, the PD-L1 protein levels were significantly increased in the epithelial layers of T-OLP (p = 0.007), but not in its subepithelial layers (p = 0.25). Importantly, increased PD-L1 levels were significantly associated to malignant transformation within 5 years. Conclusion: Increased levels of PD-1 and PD-L1 are related to malignant transformation in OLP and may represent a promising prognostic indicator to determine the risk of malignant progression of OLP. Increased PD-L1 levels might establish an immunosuppressive microenvironment, which could favor immune escape and thereby contribute to malignant transformation. Hence, checkpoint inhibitors could counteract tumor development in OLP and may serve as efficient therapeutic strategy in patients with high-risk precancerous lesions.

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Evolving Treatment of Advanced Urothelial Cancer

Journal of Oncology Practice ◽

10.1200/jop.2017.022137 ◽

2017 ◽

Vol 13 (5) ◽

pp. 309-315 ◽

Cited By ~ 13

Author(s):

Srikala S. Sridhar

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Metastatic Disease ◽

Urothelial Cancer ◽

Checkpoint Inhibitors ◽

Performance Status ◽

Standard Of Care ◽

The United States ◽

Poor Performance Status ◽

Cancer Of The Bladder

Urothelial cancer of the bladder is a smoking-related cancer and the fifth most common cancer in the United States. At presentation, up to 25% of patients will have muscle-invasive disease and, despite cystectomy or bladder-sparing trimodality approaches, will develop metastatic disease. Cisplatin-based combination chemotherapy regimens remain the standard of care in first-line metastatic disease. Although response rates to these regimens are high, they are rarely durable, and median overall survival is only 12 to 15 months. Treatment options following progression on cisplatin-based regimens or for patients unfit for cisplatin due to poor performance status, impaired renal function, or comorbidities have been quite limited. However, there is now a new class of drugs known as immune checkpoint inhibitors, which target the programmed cell death 1/programmed cell death-ligand 1 axis and promote antitumor immunity, that are showing both efficacy and tolerability. These drugs have now been approved for use in both cisplatin-treated and most recently cisplatin-unfit patients. Clinical trials are currently ongoing to determine how best to use these drugs and whether they should be used alone or in combination with other treatments. This review will discuss the current standard of care in the management of urothelial cancer and highlight recent trials of immunotherapy in this disease.

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From clinical trials to clinical use of checkpoint inhibitors for patients with metastatic urothelial cancer

Immunotherapy ◽

10.2217/imt-2020-0128 ◽

2021 ◽

Vol 13 (1) ◽

pp. 67-77

Author(s):

Rosa Tambaro ◽

Marilena Di Napoli ◽

Carmela Pisano ◽

Sabrina Chiara Cecere ◽

Laura Attademo ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Urothelial Cancer ◽

Unmet Needs ◽

Checkpoint Inhibitors ◽

Slight Improvement ◽

Metastatic Urothelial Cancer ◽

Advanced Urothelial Cancer ◽

Improvement In Survival ◽

Cell Death Protein

Monoclonal antibodies targeting the checkpoint inhibitors (CPIs), programmed cell death protein-1 or programmed cell death ligand-1, are changing the landscape of urothelial carcinoma therapeutics. Overall, clinical studies in metastatic or advanced urothelial cancer showed that CPIs provided a slight improvement in survival and a relevant advantage in safety, compared with chemotherapy. After reviewing published and ongoing trials, the authors discuss expected answers to unmet needs, with a special attention to the research of biological markers for patients with urothelial cancer eligible for treatment with CPIs in this article.

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Immunotherapy for hepatocellular carcinoma: recent advances and future perspectives

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835919862692 ◽

2019 ◽

Vol 11 ◽

pp. 175883591986269 ◽

Cited By ~ 23

Author(s):

Weiqi Xu ◽

Ken Liu ◽

Minjiang Chen ◽

Jin-Yu Sun ◽

Geoffrey W McCaughan ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Cell Death ◽

Programmed Cell Death ◽

Phase I ◽

Checkpoint Inhibitors ◽

Killer Cell ◽

Objective Response ◽

Phase Iii ◽

Future Research ◽

Advanced Hcc

The introduction of immunotherapies has been a major development in the treatment of many advanced cancers, including hepatocellular carcinoma (HCC). We are entering a new era of systemic therapy for advanced HCC associated with an explosion of clinical trial activity. Data from phase I/II studies of checkpoint inhibitors in advanced HCC have been promising, with durable objective response rates of approximately 20% seen (in both first- and second-line settings) and acceptable safety profiles (including immune-mediated hepatitis). Phase III studies evaluating anti-programmed cell death protein 1 (anti-PD-1) and anti-programmed cell death ligand 1 (anti-PD-L1) antibodies compared with sorafenib are already underway. The potential synergistic effects of anti-PD-1/anti-PD-L1 when used in combination with agents against other checkpoint molecules, systemic therapies, as well as conventional surgical and locoregional therapies are also being explored in upcoming clinical trials. Aside from this, other strategies to harness the immune system, including chimeric antigen receptor-engineered T cells, natural killer cell therapies, and peptide vaccines directed against HCC antigens have entered phase I/II studies. Current limitations of immunotherapies and areas of future research include the accurate assessment and prediction of tumor response, overcoming the immunosuppressive effects of a hypoxic microenvironment, and the management of immune-related hepatitis in patients who already have limited liver reserve.

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Phase IA/IB study of single-agent tislelizumab, an investigational anti-PD-1 antibody, in solid tumors

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2019-000453 ◽

2020 ◽

Vol 8 (1) ◽

pp. e000453 ◽

Cited By ~ 5

Author(s):

Jayesh Desai ◽

Sanjeev Deva ◽

Jong Seok Lee ◽

Chia-Chi Lin ◽

Chia-Jui Yen ◽

...

Keyword(s):

Cell Death ◽

Antitumor Activity ◽

Programmed Cell Death ◽

Solid Tumors ◽

Single Agent ◽

Objective Response ◽

Tolerability Profile ◽

Advanced Solid Tumors ◽

Antitumor Effects ◽

Phase Ib

BackgroundThe programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) axis plays a central role in suppressing antitumor immunity; axis dysregulation can be used by cancer cells to evade the immune system. Tislelizumab, an investigational monoclonal antibody with high affinity and binding specificity for PD-1, was engineered to minimize binding to FcγR on macrophages to limit antibody-dependent phagocytosis, a potential mechanism of resistance to anti-PD-1 therapy. The aim of this phase IA/IB study was to investigate the safety/tolerability, antitumor effects and optimal dose and schedule of tislelizumab in patients with advanced solid tumors.MethodsPatients (aged ≥18 years) enrolled in phase IA received intravenous tislelizumab 0.5, 2, 5 or 10 mg/kg every 2 weeks; 2 or 5 mg/kg administered every 2 weeks or every 3 weeks; or 200 mg every 3 weeks; patients in phase IB received 5 mg/kg every 3 weeks. Primary objectives were to assess tislelizumab’s safety/tolerability profile by adverse event (AE) monitoring and antitumor activity using RECIST V.1.1. PD-L1 expression was assessed retrospectively with the VENTANA PD-L1 (SP263) Assay.ResultsBetween May 2015 and October 2017, 451 patients (n=116, IA; n=335, IB) were enrolled. Fatigue (28%), nausea (25%) and decreased appetite (20%) were the most commonly reported AEs. Most AEs were grade 1–2 severity; anemia (4.9%) was the most common grade 3–4 AE. Treatment-related AEs led to discontinuation in 5.3% of patients. Grade 5 AEs were reported in 14 patients; 2 were considered related to tislelizumab. Pneumonitis (2%) and colitis (1%) were the most common serious tislelizumab-related AEs. As of May 2019, 18% of patients achieved a confirmed objective response in phase IA and 12% in phase IB; median follow-up duration was 13.6 and 7.6 months, respectively. Pharmacokinetics, safety and antitumor activity obtained from both phase IA and IB determined the tislelizumab recommended dose; ultimately, tislelizumab 200 mg intravenous every 3 weeks was the dose and schedule recommended to be taken into subsequent clinical trials.ConclusionsTislelizumab monotherapy demonstrated an acceptable safety/tolerability profile. Durable responses were observed in heavily pretreated patients with advanced solid tumors, supporting the evaluation of tislelizumab 200 mg every 3 weeks, as monotherapy and in combination therapy, for the treatment of solid tumors and hematological malignancies.Trial registration numberNCT02407990.

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284 Real World Data of Sequencing Immune Checkpoint Inhibitors (ICI) after Initial ICI

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0284 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A310-A310

Author(s):

Krishna Gunturu ◽

Muhammad Awidi ◽

Rojer Ranjit ◽

Brendan Connell ◽

Rachel Carrasquillo ◽

...

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Real World ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Medical Center ◽

Clear Understanding ◽

Real World Data ◽

World Data

BackgroundICI revolutionized modern Oncology landscape and being utilized in metastatic to adjuvant and neo-adjuvant settings. As Oncologists, we are treating cancer patients with ICI every day, yet there is still a lot that is unknown about these drugs. We don’t have clear understanding of the efficacy and toxicity when sequencing one ICI for another. We conducted a retrospective review of real world data at Lahey Hospital and Medical Center to understand further and to pave path for prospective studies to understand this issue further to improve patient care.MethodsWe retrospectively reviewed Oncology patient charts who received ICI between January1, 2014 to December 18, 2018. Total 483 patients received ICI during this time frame and 22 of these patients received a second ICI either as monotherapy or in combination with other ICI or chemotherapy.ResultsA total of 22 patients received subsequent ICI after the initial ICI as showed in table 1. 15 of the 22 (68%) patients were transitioned from one ICI to another monotherapy. 11 of these patients were transitioned secondary to disease progression (73%), three had immune related adverse events and one was switched per standard of care. One patient had ICI re-challenge. Three patients had a transition from ICI monotherapy to combination ICI therapy. One patient went onto chemo-immunotherapy and 2 patients transitioned from combination ICI to chemo-immunotherapy.Abstract 284 Table 1Real world data of sequencing immune checkpoint inhibitors (ICI) after initial ICIConclusionsICI therapy is evolving and patients are being treated with multiple lines of ICI. In current practices, ICI is frequently being transitioned from cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD-1) or its ligand, programmed cell death ligand 1 (PD-L1) classes or combined with chemotherapy or targeted therapy. It would be prudent to explore the effects of sequencing these medications either as a monotherapy or in combination with other therapies to better serve our patients and to prevent financial toxicity.

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Predicting Responses to Checkpoint Inhibitors in Lymphoma: Are We Up to the Standards of Solid Tumors?

Clinical Medicine Insights Oncology ◽

10.1177/1179554920976366 ◽

2020 ◽

Vol 14 ◽

pp. 117955492097636

Author(s):

Ah-Reum Jeong ◽

Edward D Ball ◽

Aaron Michael Goodman

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

B Cell ◽

Solid Tumors ◽

Cell Lymphoma ◽

Checkpoint Inhibitors ◽

B Cell Lymphoma ◽

Hematologic Malignancies ◽

Checkpoint Blockade ◽

Programmed Cell Death 1

Treatment of cancer has transformed with the introduction of checkpoint inhibitors. However, the majority of solid tumor patients do not respond to checkpoint blockade. In contrast, the response rate to programmed cell death 1 (PD-1) blockade in relapsed/refractory classical Hodgkin lymphoma (cHL) is 65% to 84% which is the highest among all cancers. Currently, checkpoint inhibitors are only approved for cHL and primary mediastinal B-cell lymphoma as the responses to single-agent checkpoint blockade in other hematologic malignancies is disappointingly low. Various established biomarkers such as programmed cell death 1 ligand 1 (PD-L1) protein surface expression, mismatch repair (MMR) status, and tumor mutational burden (TMB) are routinely used in clinical decision-making in solid tumors. In this review, we will explore these biomarkers in the context of hematologic malignancies. We review characteristic 9p24.1 structural alteration in cHL and primary mediastinal B-cell lymphoma (PMBCL) as a basis for response to PD-1 inhibition, as well as the role of antigen presentation pathways. We also explore the reported frequencies of MMR deficiency in various hematologic malignancies and investigate TMB as a predictive marker.

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Immune Checkpoint Inhibitors in Urothelial Carcinoma: Recommendations for Practical Approaches to PD-L1 and Other Potential Predictive Biomarker Testing

Cancers ◽

10.3390/cancers13061424 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1424

Author(s):

Antonio Lopez-Beltran ◽

Fernando López-Rios ◽

Rodolfo Montironi ◽

Sophie Wildsmith ◽

Markus Eckstein

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Best Practice ◽

Checkpoint Inhibitors ◽

Predictive Biomarker ◽

High Quality ◽

The Status ◽

Biomarker Testing ◽

Novel Biomarkers ◽

Scoring Algorithms

Immuno-oncology (IO) agents (anti–programmed cell death 1 (PD-1) and anti–programmed cell death-ligand 1 (PD-L1)) are approved as first- and second-line treatments for metastatic UC. PD-L1 expression levels in UC tumors help clinicians determine which patients are more likely to respond to IO therapies. Assays for approved IO agents use different antibodies, immunohistochemical protocols, cutoffs (defining “high” vs. “low” PD-L1 expression), and scoring algorithms. The robust control of pre-analytical and analytical standards is needed to obtain high-quality PD-L1 results. To better understand the status and perspectives of biomarker-guided patient selection for anti–PD-1 and anti–PD-L1 agents in UC, three workshops were held from December 2018 to December 2019 in Italy, Malaysia, and Spain. The primary goal was to develop recommendations for best practice approaches to PD-L1 testing in UC. Recommendations pertaining to the interpretation and reporting of the results of PD-L1 assays from experienced pathologists and oncologists from around the globe are included. A test request form for pathology laboratories was developed as a critical first step for oncologists/urologists to encourage communication between clinicians and pathologists, ensuring fast and high-quality test results. In this era of personalized medicine, we briefly discuss novel biomarkers being evaluated for IO agents in UC.

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Clinical Applications of Immunotherapy Combination Methods and New Opportunities for the Future

BioMed Research International ◽

10.1155/2017/1623679 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Ece Esin

Keyword(s):

Cell Death ◽

Programmed Cell Death ◽

Checkpoint Inhibitors ◽

Innate Immune ◽

Small Subset ◽

New Class ◽

Combination Strategies ◽

Combination Methods ◽

Immune Editing ◽

Cell Death Protein

In the last decade, we have gained a deeper understanding of innate immune system. The mechanism of the continuous guarding of progressive mutations happening in a single cell was discovered and the production and the recognition of tumor associated antigens by the T-cells and elimination of numerous tumors by immune-editing were further understood. The new discoveries on immune mechanisms and its relation with carcinogenesis have led to development of a new class of drugs called immunotherapeutics. T lymphocyte-associated antigen 4, programmed cell death protein 1, and programmed cell death protein ligand 1 are the classes drugs based on immunologic manipulation and are collectively known as the “checkpoint inhibitors.” Checkpoint inhibitors have shown remarkable antitumor efficacy in a broad spectrum of malignancies; however, the strongest and most durable immune responses do not last long and the more durable responses only occur in a small subset of patients. One of the solutions which have been put forth to overcome these challenges is combination strategies. Among the dual use of methods, a backbone with either PD-1 or PD-L1 antagonist drugs alongside with certain cytotoxic chemotherapies, radiation, targeted drugs, and novel checkpoint stimulators is the most promising approach and will be on stage in forthcoming years.

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