The development of immune checkpoint inhibitors has changed the treatment paradigm for advanced cancers across many tumor types. Despite encouraging and sometimes durable responses in a subset of ...patients, most patients do not respond. Tumors have adopted the PD-1/PD-L1 axis for immune escape to facilitate tumor growth, which can be leveraged as a potential target for immune checkpoint inhibitors. On this basis, PD-L1 protein expression on tumor or immune cells emerged as the first potential predictive biomarker for sensitivity to immune checkpoint blockade. The goal of our study was to evaluate PD-L1 as a predictive biomarker based on all US Food and Drug Administration (FDA) drug approvals of immune checkpoint inhibitors. We evaluated the primary studies associated with 45 FDA drug approvals from 2011 until April 2019. In total, there were approvals across 15 tumor types. Across all approvals, PD-L1 was predictive in only 28.9% of cases, and was either not predictive (53.3%) or not tested (17.8%) in the remaining cases. There were 9 FDA approvals linked to a specific PD-L1 threshold and companion diagnostic: bladder cancer (N = 3), non-small cell lung cancer (N = 3), triple-negative breast cancer (N = 1), cervical cancer (N = 1), and gastric/gastroesophageal junction cancer (N = 1) with 8 of 9 (88.9%) with immune checkpoint inhibitor monotherapy. The PD-L1 thresholds were variable both within and across tumor types using several different assays, including approvals at the following PD-L1 thresholds: 1, 5, and 50%. PD-L1 expression was also measured in a variable fashion either on tumor cells, tumor-infiltrating immune cells, or both. In conclusion, our findings indicate that PD-L1 expression as a predictive biomarker has limitations and that the decision to pursue testing must be carefully implemented for clinical decision-making.
Purpose
Stress-induced adrenergic signaling can suppress the immune system. In animal models, pharmacological beta-blockade stimulates CD8 + T-cell activity and improves clinical activity of immune ...checkpoint blockade (ICB) in inhibiting tumor growth. Herein, we investigated the effect of BB on clinical outcomes of patients receiving ICB in advanced solid tumors.
Methods
We retrospectively evaluated patients with solid tumors treated with ICB at our institution from January 1, 2011 to April 28, 2017. The primary clinical outcome was disease control. Secondary clinical outcomes were overall survival (OS), and duration of therapy (DoT). The primary predictor was use of BB. Association between disease control status and BB use was assessed in univariable and multivariable logistic regression. OS was calculated using hazard ratios of BB-recipient patients vs. BB non-recipient patients via Cox proportional hazards regression models. All tests were two-sided at a significance level of 0.05.
Results
Of 339 identified patients receiving ICB, 109 (32%) also received BB. In covariate-adjusted analysis, odds of disease control were significantly higher among BB recipients compared to BB-non-recipients (2.79; 1.54–5.03;
P
= 0.001). While we did not observe significant association of OS with the use of BB overall, significant association with better OS was observed for the urothelial carcinoma cohort (HR: 0.24; 0.09, 0.62;
P
= 0.0031).
Conclusions
Concurrent use of BB may enhance the clinical activity of ICB and influence overall survival, particularly in patients with urothelial carcinoma. Our findings warrant further investigation to understand the interaction of beta adrenergic signaling and antitumor immune activity and explore a combination strategy.
Chemotherapy may exert immunomodulatory effects, thereby combining favorably with the immune checkpoint blockade. The pharmacodynamic effects of such combinations, and potential predictive ...biomarkers, remain unexplored.
To determine the safety, efficacy, and immunomodulatory effects of gemcitabine and cisplatin (GC) plus ipilimumab and explore the impact of somatic DNA damage response gene alterations on antitumor activity.
Multicenter single arm phase 2 study enrolling 36 chemotherapy-naïve patients with metastatic urothelial cancer. Peripheral blood flow cytometry was performed serially on all patients and whole exome sequencing of archival tumor tissue was performed on 28/36 patients.
Two cycles of GC followed by four cycles of GC plus ipilimumab.
The primary endpoint was 1-yr overall survival (OS). Secondary endpoints included safety, objective response rate, and progression-free survival.
Grade ≥3 adverse events occurred in 81% of patients, the majority of which were hematologic. The objective response rate was 69% and 1-yr OS was 61% (lower bound 90% confidence interval: 51%). On exploratory analysis, there were no significant changes in the composition and frequency of circulating immune cells after GC alone. However, there was a significant expansion of circulating CD4 cells with the addition of ipilimumab which correlated with improved survival. The response rate was significantly higher in patients with deleterious somatic DNA damage response mutations (sensitivity=47.6%, specificity=100%, positive predictive value=100%, and negative predictive value=38.9%). Limitations are related to the sample size and single-arm design.
GC+ipilimumab did not achieve the primary endpoint of a lower bound of the 90% confidence interval for 1-yr OS of >60%. However, within the context of a small single-arm trial, the results may inform current approaches combining chemotherapy plus immunotherapy from the standpoint of feasibility, appropriate cytotoxic backbones, and potential predictive biomarkers. Trial registration: ClinicalTrials.gov NCT01524991.
Combining chemotherapy and immune checkpoint blockade in patients with metastatic urothelial cancer is feasible. Further studies are needed to refine optimal combinations and evaluate tests that might identify patients most likely to benefit.
Administration of gemcitabine and cisplatin plus immune checkpoint blockade is feasible and concurrent chemotherapy does not preclude immunomodulatory effects. Tumors with DNA damage response gene mutations may be particularly sensitive to this approach.
Androgen receptor-targeted therapies (ARTs) improve survival outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC); however, a significant portion of patients discontinue ...treatment for various reasons including treatment-related toxicity. We aim to describe reasons for ART treatment discontinuation and identify predictors associated with increased risk of treatment discontinuation due to toxicity.
We performed a single-institution retrospective review of patients with mCRPC receiving ART between 2010 and 2021. Our primary aim was to identify risk factors for treatment discontinuation due to toxicity. Our secondary aim was to describe ART discontinuation patterns among patients with mCRPC.
One hundred thirty-three patients with mCRPC started and discontinued ARTs. Fourteen patients (10.5%) discontinued treatment due to toxicity. Common reasons for treatment discontinuation include Prostate Specific Antigen test progression, radiographic progression, toxicity, and death. Significant predictors of treatment discontinuation due to toxicity on bivariate analysis and multivariate analysis included patient-reported falls (odds ratio OR: 7.67, CI: 1.31-40.42; P =0.016), rash (OR: 13.4, CI: 1.35-134.81; P =0.026), and weakness (OR: 4.16, CI: 1.15-15.0; P =0.019).
Our work presents the first description of ART treatment discontinuation and its causes in the real-world setting, as well as patient-reported side effects. Most patients with mCRPC discontinued treatment due to the progression of disease and a minority of patients discontinued secondary to treatment toxicity. Initial multivariable analysis suggests that patient-reported weakness, falls, and rash were associated with a higher likelihood of treatment discontinuation due to toxicity. Early monitoring of this population can prolong the duration of treatment and prevent unnecessary treatment burden.
Several anti-programmed death-1 (anti-PD-1) and anti-programmed death ligand-1 (anti-PD-L1) antibodies have been approved by regulatory authorities for treatment of platinum-resistant metastatic ...urothelial cancer (mUC). The impact of these therapies on survival, and comparability of PD-1 versus PD-L1 blockade are unknown.
To determine the restricted mean survival time (RMST) of patients with platinum-resistant mUC treated with PD-1/PD-L1 inhibitors and to compare RMSTs in patients treated with PD-1 versus PD-L1 inhibitors.
We searched for phase 1, 2, and 3 clinical trials that assessed PD-1 or PD-L1 inhibition for patients with platinum-resistant mUC. Literature review and study selection, data abstraction, and risk of bias assessment were performed by two reviewers. Survival data were reconstructed using an algorithm that derives individual time-to-event data from published Kaplan-Meier curves. The RMST with 95% confidence interval (CIs) was calculated.
From 836 references, six clinical trials were included. Survival data were reconstructed for 1315 and 736 patients treated with PD-1/PD-L1 inhibitors and chemotherapy, respectively. The RMSTs with PD-1/PD-L1 blockade up to 12 and 18mo of follow-up were 7.8mo (95% CI 7.6, 8.1) and 10mo (95% CI 9.7, 10.5), respectively. A network meta-analysis of two randomized trials revealed no significant difference in the RMST up to 18mo with PD-1 versus PD-L1 blockade (1.0mo; 95% CI −0.5, 2.3mo). Using reconstructed survival data from all six trials, the RMSTs with PD-1 versus PD-L1 blockade up to 12 and 18mo follow-up were 7.8mo (95% CI 7.7, 8.2) versus 7.8mo (95% CI 7.5, 8.2) and 10.1mo (95% CI 9.6, 10.7) versus 10mo (95% CI 9.5, 10.6), respectively.
Our RMST estimates may be used as benchmarks to contextualize survival outcomes and inform future trial design with PD-1/PD-L1 inhibitors. PD-1 versus PD-L1 blockade in patients with mUC yields comparable survival outcomes.
In this study, we found that outcomes for patients with metastatic bladder cancer treated with programmed death-1 and programmed death ligand-1 inhibitors, who received prior platinum-based chemotherapy, were similar.
Restricted mean survival time estimates may be used to benchmark survival outcomes and inform future trial design.Programmed death-1 and programmed death ligand-1 blockade in patients with platinum-resistant metastatic urothelial cancer yield comparable survival outcomes.
Background
The data of head-to-head comparisons of the effect of bone-modifying agents (BMAs) in patients with androgen deprivation therapy (ADT) for prostate cancer without skeletal metastasis is ...limited. Thus, we conducted a network meta-analysis to compare each BMA for the efficacy of bone mineral densities (BMDs) and the risk of fracture.
Methods
We performed a network meta-analysis to compare the change of BMDs and the risk of vertebral fracture in the studies included using a random-effect model. The primary outcomes are the change of BMD of the lumbar spine (LS) and the total hip (TH) from the baseline at 1 year from the initiation of the BMA and the risk of vertebral fracture.
Results
We identified and included 15 studies in this analysis. All BMAs except risedronate showed a significant increase of BMD of the LS compared with groups without BMA, among which zoledronate showed the most BMD gain. At TH, bisphosphonates (alendronate, pamidronate, and zoledronate) and denosumab showed significant elevation compared with the no-BMA group. Denosumab was associated with the most BMD gain at the TH. Only denosumab reduced the risk of vertebral fracture (relative risk 95% confidence interval: 0.40 0.20–0.81). Although zoledronate showed the highest BMD gain at the LS, it did not reduce the risk of vertebral fracture in this analysis.
Conclusion
Most bisphosphonates and denosumab significantly increased BMD at the LS and the TH in patients receiving ADT for prostate cancer without skeletal metastasis. In particular, zoledronate and denosumab were the most potent BMAs in terms of BMD increment at the LS and the TH, respectively. However, denosumab, not zoledronate, was the only BMA that showed a significant risk reduction of vertebral fracture. We need further studies to examine the change of bone quality and the effect on the risk of non-vertebral and hip fractures.
Prostate cancer exists in a clinical continuum of hormone-sensitive to castration-resistant disease. Despite the use of chemotherapy and androgen synthesis inhibitors in the castration-resistant ...setting, this remains a lethal disease. The advent of immune checkpoint blockade has changed the outlook for cancer treatment and survival for several tumors since its first approval in 2011; however, the clinical benefit in castration-resistant prostate cancer (CRPC) is rather limited. Currently, Sipuleucel-T remains the only immune modality to be approved in CRPC setting. Such immune resistance likely exists due to low immunogenicity of prostate tumor cells and an immunosuppressive tumor microenvironment. In this review, we describe the early experiences of immune checkpoint blockade and therapeutic vaccines in CRPC. We then outline strategies currently being implemented to overcome immune resistance, as well as genomic biomarker investigation to identify patients that may harbor more immunogenic tumors. At last, we preview emerging immunotherapeutic platforms.
Prostate cancer has a variable clinical course, ranging from curable local disease to lethal metastatic spread. Eradicating metastatic cells is a unique challenge that is rarely met with the ...available therapies. Thus, targeting prostate cancer cells in earlier disease states is a crucial window of opportunity. Interestingly, cancer cells migrate from their primary site during pre-cancerous and malignant phases to seed secondary organs. These cells, known as disseminated cancer cells (DCCs), may remain dormant for months or decades before activating to form metastases. Bone marrow, a dormancy-permissive site, is the major organ for housed DCCs and eventual metastases in prostate cancer. The dynamic interplay between DCCs and the primary tumor microenvironment (TME), as well as that between DCCs and the secondary organ niche, controls the conversion between states of dormancy and activation. Here, we discuss recent discoveries that have improved our understanding of dormancy signaling and the role of the TME in modulating the epigenetic reprogramming of DCCs. We offer potential strategies to target DCCs in prostate cancer.
Abstract Alkaptonuria is disorder of tyrosine metabolism due to deficiency of homogentisic oxidase characterized by excretion of homogentisic acid in urine, deposition of oxidized homogensitate ...pigments in connective tissues and articular cartilages (ochronosis). The result is dark pigmentation and weakening of the tissues resulting in chronic inflammation and osteoarthritis. Management of alkaptonuric ochronic osteoarthritis is usually symptomatic and replacements have comparable outcomes to osteoarthritis in patients without ochronosis. I report a case of a patient with ochronosis of knee treated with total knee replacement and report operative pearls for surgery in this rare disorder.
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