Summary Background Patients with metastatic urothelial carcinoma have a dismal prognosis and few treatment options after first-line chemotherapy. Responses to second-line treatment are uncommon. We ...assessed nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor antibody, for safety and activity in patients with metastatic or surgically unresectable urothelial carcinoma whose disease progressed or recurred despite previous treatment with at least one platinum-based chemotherapy regimen. Methods In this multicentre, phase 2, single-arm study, patients aged 18 years or older with metastatic or surgically unresectable locally advanced urothelial carcinoma, measurable disease (according to Response Evaluation Criteria In Solid Tumors v1.1), Eastern Cooperative Oncology Group performance statuses of 0 or 1, and available tumour samples for biomarker analysis received nivolumab 3 mg/kg intravenously every 2 weeks until disease progression and clinical deterioration, unacceptable toxicity, or other protocol-defined reasons. The primary endpoint was overall objective response confirmed by blinded independent review committee in all treated patients and by tumour PD-L1 expression (≥5% and ≥1%). This trial is registered with ClinicalTrials.gov , number NCT02387996 , and is completed. Follow-up is still ongoing. Findings Between March 9, 2015, and Oct 16, 2015, 270 patients from 63 sites in 11 countries received nivolumab, and 265 were evaluated for activity. Median follow-up for overall survival was 7·00 months (IQR 2·96–8·77). Confirmed objective response was achieved in 52 (19·6%, 95% CI 15·0–24·9) of 265 patients. Confirmed objective response was achieved in 23 (28·4%, 95% CI 18·9–39·5) of the 81 patients with PD-L1 expression of 5% or greater, 29 (23·8%, 95% CI 16·5–32·3) of the 122 patients with PD-L1 expression of 1% or greater, and 23 (16·1%, 95% CI 10·5–23·1) of the 143 patients with PD-L1 expression of less than 1%. Grade 3–4 treatment-related adverse events occurred in 48 (18%) of 270 patients—most commonly grade 3 fatigue and diarrhoea, which each occurred in five patients. Three deaths were attributed to treatment (pneumonitis, acute respiratory failure, and cardiovascular failure). Interpretation Nivolumab monotherapy provided meaningful clinical benefit, irrespective of PD-L1 expression, and was associated with an acceptable safety profile in previously treated patients with metastatic or surgically unresectable urothelial carcinoma. Funding Bristol-Myers Squibb.
Introduction
Cisplatin, a platinum‐based antineoplastic agent, is the cornerstone for the treatment of many malignancies. Nephrotoxicity is the primary dose‐limiting toxicity, and various hydration ...regimens and supplementation strategies are used to prevent cisplatin‐induced kidney injury. However, evidence‐based recommendations on specific hydration regimens are limited. A systematic review was performed to evaluate clinical studies that have examined hydration and supplementation strategies to prevent cisplatin‐induced nephrotoxicity.
Materials and Methods
PubMed and Excerpta Medica databases were searched from 1966 through October 2015 for clinical trials and other studies focused on hydration regimens to prevent nephrotoxicity in cancer patients treated with cisplatin. The University of Oxford Centre for Evidence‐Based Medicine criteria were used to grade level of evidence.
Results
Among the 1,407 identified studies, 24 were included in this systematic review. All studies differed on type, volume, and duration of hydration. Among the 24 studies, 5 evaluated short‐duration hydration, 4 evaluated low‐volume hydration, 4 investigated magnesium supplementation, and 7 reviewed forced diuresis with hydration. Short‐duration and lower‐volume hydration regimens are effective in preventing cisplatin‐induced nephrotoxicity. Magnesium supplementation may have a role as a nephroprotectant, and forced diuresis may be appropriate in some patients receiving cisplatin.
Conclusion
Hydration is essential for all patients to prevent cisplatin‐induced nephrotoxicity. Specifically, short‐duration, low‐volume, outpatient hydration with magnesium supplementation and mannitol forced diuresis (in select patients) represent best practice principles for the safe use of cisplatin.
Implications for Practice
The findings contained within this systematic review show that (a) hydration is essential for all patients to prevent cisplatin‐induced nephrotoxicity, (b) short‐duration, low‐volume, outpatient hydration regimens appear to be safe and feasible, even in patients receiving intermediate‐ to high‐dose cisplatin, (c) magnesium supplementation (8–16 milliequivalents) may limit cisplatin‐induced nephrotoxicity, and (d) mannitol may be considered for high‐dose cisplatin and/or patients with preexisting hypertension. These findings have broad implications for clinical practice and represent best practice principles for the prevention of cisplatin‐induced nephrotoxicity.
Various hydration regimens and supplementation strategies are used to prevent cisplatin‐induced kidney injury; however, evidence‐based recommendations on specific hydration regimens are limited. This systematic review of the literature evaluates clinical studies that have examined hydration and supplementation strategies to prevent cisplatin‐induced nephrotoxicity.
Cancers infiltrated with T-cells are associated with a higher likelihood of response to PD-1/PD-L1 blockade. Counterintuitively, a correlation between epithelial-mesenchymal transition (EMT)-related ...gene expression and T-cell infiltration has been observed across tumor types. Here we demonstrate, using The Cancer Genome Atlas (TCGA) urothelial cancer dataset, that although a gene expression-based measure of infiltrating T-cell abundance and EMT-related gene expression are positively correlated, these signatures convey disparate prognostic information. We further demonstrate that non-hematopoietic stromal cells are a major source of EMT-related gene expression in bulk urothelial cancer transcriptomes. Finally, using a cohort of patients with metastatic urothelial cancer treated with a PD-1 inhibitor, nivolumab, we demonstrate that in patients with T-cell infiltrated tumors, higher EMT/stroma-related gene expression is associated with lower response rates and shorter progression-free and overall survival. Together, our findings suggest a stroma-mediated source of immune resistance in urothelial cancer and provide rationale for co-targeting PD-1 and stromal elements.
BACKGROUND
The enrollment of Black patients in cancer clinical trials continues to trend far below the true prevalence of disease in Black patients in the United States, limiting the generalizability ...of trial results. A potentially overlooked contributor to the underenrollment of Black patients may be the increasing enrollment of cancer trials in countries outside the United States. However, the impact of the globalization of cancer clinical trials on recruitment of racial minority patients has been understudied.
METHODS
In this study, race and accrual location data for all cancer drugs approved by the US Food and Drug Administration (FDA) between 2015 and 2018 were analyzed. A disparity score was calculated for each approval, a metric comparing Black enrollment in clinical trials with the estimated burden of disease in Black patients.
RESULTS
Of 49 global clinical trials supporting 35 FDA drug approvals with race data available, Black patients accounted for 2.5% of enrollment (range, 0%‐10%), with a median disparity score of 0.19 (range, 0.01‐0.98). In 21 clinical trials supporting 18 FDA drug approvals with both race and accrual location data available, 64% patients were enrolled outside the United States (range, 0%‐100%). Black patients accounted for 3.2% of enrollment (range, 0.2%‐10%), and the median disparity score was 0.23 (range, 0.01‐0.98). There was a significant inverse correlation between the proportion of trial patients enrolled outside the United States and the disparity score (Pearson correlation, –0.61; P = .007).
CONCLUSIONS
The globalization of cancer clinical trials is associated with a widening racial enrollment disparity gap in the United States. The impact of global trials on domestic clinical trial generalizability warrants further consideration from a regulatory and policy standpoint.
LAY SUMMARY
Black patients continue to be underrepresented in cancer clinical trials; this disparity has worsened in recent years perhaps because of the globalization of cancer clinical trials.
In an analysis of demographic information from 21 cancer clinical trials leading to US Food and Drug Administration approvals between 2015 and 2018, clinical trials conducted primarily outside the United States were 2‐fold less likely to enroll Black participants than US clinical trials.
Thus, the globalization of cancer clinical trials may have the unintended consequence of further exacerbating existing racial disparities in cancer clinical trial representation and ultimately the generalizability of trial results.
Cancer clinical trials conducted primarily outside of the United States are 2‐fold less likely to enroll Black participants than clinical trials conducted within the United States. The impact of globalization of enrollment on the generalizability of results in the United States warrants further consideration from both a regulatory and policy standpoint.
Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase involved in the regulation of many cellular processes. A confirmed tumor suppressor protein, PP2A is genetically altered or ...functionally inactivated in many cancers highlighting a need for its therapeutic reactivation. In this review we discuss recent literature on PP2A: the elucidation of its structure and the functions of its subunits, and the identification of molecular lesions and post‐translational modifications leading to its dysregulation in cancer. A final section will discuss the proteins and small molecules that modulate PP2A and how these might be used to target dysregulated forms of PP2A to treat cancers and other diseases.
PP2A, a heterotrimeric tumor suppressor protein, is genetically disrupted or functionally inactivated in cancer and other diseases. PP2A's importance derives from its central role in negatively regulating numerous oncogenic kinases. Restoring its function by targeting posttranslational modifications and endogenous inhibitory proteins can suppress cancer progression and will ultimately provide new tools for use in patients.
Given that randomized trials exploring adjuvant chemotherapy for bladder cancer have been underpowered and/or terminated prematurely, yielding inconsistent results and creating an evidence gap, we ...sought to compare the effectiveness of cystectomy versus cystectomy plus adjuvant chemotherapy in real-world patients.
We conducted an observational study to compare the effectiveness of adjuvant chemotherapy versus observation postcystectomy in patients with pathologic T3-4 and/or pathologic node-positive bladder cancer using the National Cancer Data Base. We compared overall survival using propensity score (-adjusted, -stratified, -weighted, and -matched) analyses based on patient-, facility-, and tumor-level characteristics. A sensitivity analysis was performed to examine the impact of performance status.
A total of 5,653 patients met study inclusion criteria; 23% received adjuvant chemotherapy postcystectomy. Chemotherapy-treated patients were younger and more likely to have private insurance, live in areas with a higher median income and higher percentage of high school-educated residents, and have lymph node involvement and positive surgical margins (P < .05 for all comparisons). Stratified analyses adjusted for propensity score demonstrated an improvement in overall survival with adjuvant chemotherapy (hazard ratio, 0.70; 95% CI, 0.64 to 0.76), and similar results were achieved with propensity score matching and weighting. The association between adjuvant chemotherapy and improved survival was consistent in subset analyses and was robust to the effects of poor performance status.
In this observational study, adjuvant chemotherapy was associated with improved survival in patients with locally advanced bladder cancer. Although neoadjuvant chemotherapy remains the preferred approach based on level I evidence, these data lend further support for the use of adjuvant chemotherapy in patients with locally advanced bladder cancer postcystectomy who did not receive chemotherapy preoperatively.
Metastatic castration-resistant prostate cancer (mCRPC) is immunologically “cold” and predominantly resistant to immune checkpoint therapy due to few tumor-infiltrating T cells. Ipilimumab ...(anti-CTLA-4) or anti-PD-1/PD-L1 monotherapy failed to show a significant benefit. Although the PD-1/PD-L1 pathway is minimally expressed in prostate tumors, we previously demonstrated that PD-1/PD-L1 expression increases as a compensatory inhibitory pathway in parallel with an ipilimumab-induced increase in tumor-infiltrating T cells. Here, we report the largest trial to date in mCRPC with anti-CTLA-4 plus anti-PD-1 (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg; CheckMate 650, NCT02985957). With median follow-ups of 11.9 and 13.5 months in cohorts 1 (pre-chemotherapy; n = 45) and 2 (post-chemotherapy; n = 45), objective response rate was 25% and 10%, and median overall survival was 19.0 and 15.2 months, respectively. Four patients, two in each cohort, had complete responses. Exploratory studies identify potential biomarkers of response. Grade 3–4 treatment-related adverse events have occurred in ∼42%–53% of patients, with four treatment-related deaths. Therefore, dose/schedule modifications have been implemented.
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•We found 25% ORR in pre-chemotherapy cohort 1 and 10% ORR in post-chemotherapy cohort 2•We report 5.5 and 3.8 months median rPFS and 19.0 and 15.2 months median OS•Exploratory analyses identify potential biomarkers of response•Study expansion is needed to assess other dosing regimens
From a preliminary phase II clinical trial on metastatic castration-resistant prostate cancer with anti-CTLA-4 plus anti-PD-1, Sharma et al. report ORR of 25% and 10%, median rPFS of 5.5 and 3.8 months, and median OS of 19.0 and 15.2 months in pre- and post-chemotherapy patients. Additional analyses with modified dosing are needed to optimize safety.
Objective
To describe the natural history of untreated muscle‐invasive bladder cancer (MIBC) and compare the oncological outcomes of treated and untreated patients.
Patients and Methods
We utilised a ...database encompassing all patients with newly diagnosed bladder cancer in Stockholm, Sweden between 1995 and 1996. The median follow‐up for survivors was 14.4 years. Overall, 538 patients were diagnosed with bladder cancer of whom 126 had clinically localised MIBC. Patients were divided into two groups: those who received radical cystectomy or radiation therapy, and those who did not receive any form of treatment. Multivariable Cox or competing‐risks regressions were adopted to predict metastasis, overall survival (OS), and cancer‐specific mortality (CSM), when appropriate. Analyses were adjusted for age at diagnosis, sex, tumour stage, clinical N stage, and treatment.
Results
In all, 64 (51%) patients did not receive any definitive local treatment. In the untreated group, the median (interquartile range) age at diagnosis was 79 (63–83) vs 69 (63–74) years in the treated group (P < 0.001). Overall, 109 patients died during follow‐up. At 6 months after diagnosis, 38% of the untreated patients had developed metastatic disease and 41% had CSM. The 5‐year OS rate for untreated and treated patients was 5% (95% confidence interval CI 1, 12%) vs 48% (95% CI 36, 60%), respectively. Patients not receiving any treatment had a 5‐year cumulative incidence of CSM of 86% (95% CI 75, 94%) vs 48% (95% CI 36, 60%) for treated patients. Untreated patients had a higher risk of progression to metastatic disease (hazard ratio HR 2.40, 95% CI 1.28, 4.51; P = 0.006), death from any cause (HR 2.63, 95% CI 1.65, 4.19; P < 0.001) and CSM (subdistribution HR 2.02, 95% CI 1.24, 3.30; P = 0.004).
Conclusions
Untreated patients with MIBC are at very high risk of near‐term CSM. These findings may help balance the risks vs benefits of integrating curative intent therapy particularly in older patients with MIBC.
Atezolizumab can induce sustained responses in metastatic urothelial carcinoma. We report the results of IMvigor130, a phase 3 trial that compared atezolizumab with or without platinum-based ...chemotherapy versus placebo plus platinum-based chemotherapy in first-line metastatic urothelial carcinoma.
In this multicentre, phase 3, randomised trial, untreated patients aged 18 years or older with locally advanced or metastatic urothelial carcinoma, from 221 sites in 35 countries, were randomly assigned to receive atezolizumab plus platinum-based chemotherapy (group A), atezolizumab monotherapy (group B), or placebo plus platinum-based chemotherapy (group C). Patients received 21-day cycles of gemcitabine (1000 mg/m2 body surface area, administered intravenously on days 1 and 8 of each cycle), plus either carboplatin (area under the curve of 4·5 mg/mL per min administered intravenously) or cisplatin (70 mg/m2 body surface area administered intravenously) on day 1 of each cycle with either atezolizumab (1200 mg administered intravenously on day 1 of each cycle) or placebo. Group B patients received 1200 mg atezolizumab, administered intravenously on day 1 of each 21-day cycle. The co-primary efficacy endpoints for the intention-to-treat population were investigator-assessed Response Evaluation Criteria in Solid Tumours 1.1 progression-free survival and overall survival (group A vs group C) and overall survival (group B vs group C), which was to be formally tested only if overall survival was positive for group A versus group C. The trial is registered with ClinicalTrials.gov, NCT02807636.
Between July 15, 2016, and July 20, 2018, we enrolled 1213 patients. 451 (37%) were randomly assigned to group A, 362 (30%) to group B, and 400 (33%) to group C. Median follow-up for survival was 11·8 months (IQR 6·1–17·2) for all patients. At the time of final progression-free survival analysis and interim overall survival analysis (May 31, 2019), median progression-free survival in the intention-to-treat population was 8·2 months (95% CI 6·5–8·3) in group A and 6·3 months (6·2–7·0) in group C (stratified hazard ratio HR 0·82, 95% CI 0·70–0·96; one-sided p=0·007). Median overall survival was 16·0 months (13·9–18·9) in group A and 13·4 months (12·0–15·2) in group C (0·83, 0·69–1·00; one-sided p=0·027). Median overall survival was 15·7 months (13·1–17·8) for group B and 13·1 months (11·7–15·1) for group C (1·02, 0·83–1·24). Adverse events that led to withdrawal of any agent occurred in 156 (34%) patients in group A, 22 (6%) patients in group B, and 132 (34%) patients in group C. 50 (11%) patients in group A, 21 (6%) patients in group B, and 27 (7%) patients in group C had adverse events that led to discontinuation of atezolizumab or placebo.
Addition of atezolizumab to platinum-based chemotherapy as first-line treatment prolonged progression-free survival in patients with metastatic urothelial carcinoma. The safety profile of the combination was consistent with that observed with the individual agents. These results support the use of atezolizumab plus platinum-based chemotherapy as a potential first-line treatment option for metastatic urothelial carcinoma.
F Hoffmann-La Roche and Genentech.
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