Dataset Information

Effectiveness of First-line Immune Checkpoint Blockade Versus Carboplatin-based Chemotherapy for Metastatic Urothelial Cancer.

ABSTRACT:

Background

Limited data compare first-line carboplatin-based chemotherapy and immune checkpoint blockade in cisplatin-ineligible metastatic urothelial carcinoma (mUC) patients. The primary evidence guiding treatment decisions was a recent Food and Drug Administration/European Medicines Agency safety alert based on emerging data from two ongoing phase III trials, reporting shorter survival in programmed death-ligand 1 (PD-L1)-negative patients receiving immunotherapy. Final results from these trials are unknown.

Objective

To compare survival in cisplatin-ineligible mUC patients receiving first-line immunotherapy versus those receiving carboplatin-based chemotherapy.

Design, setting, and participants

We conducted a retrospective cohort study of 2017 mUC patients receiving first-line carboplatin-based chemotherapy (n = 1530) or immunotherapy (n = 487) from January 1, 2011 to May 18, 2018 using the Flatiron Health electronic health record-derived database.

Outcome measurements and statistical analysis

The primary outcomes were overall survival (OS), comparing 12- and 36-mo OS, and hazard ratios before and after 12 mo. Propensity score-based inverse probability of treatment weighting (IPTW) was used to address confounding in Kaplan-Meier and Cox regression model estimates of comparative effectiveness.

Results and limitations

IPTW-adjusted OS rates in the immunotherapy group were lower at 12 mo (39.6% [95% confidence interval {CI} 34.0-45.3%] vs 46.1% [95% CI 43.4-48.8%]) but higher at 36 mo (28.3% [95% CI 21.8-34.7%] vs 13.3% [95% CI 11.1-15.5%]) relative to the chemotherapy group. Immunotherapy treatment demonstrated inferior OS during the first 12 mo relative to carboplatin-based chemotherapy (IPTW-adjusted hazard ratio [HR] 1.37, 95% CI 1.15-1.62), but superior OS beyond 12 mo (IPTW-adjusted HR 0.50, 95% CI 0.30-0.85). Limitations include retrospective design and potential unmeasured confounding.

Conclusions

In the setting of mUC, clinicians and patients should carefully consider how to balance the short-term benefit of chemotherapy against the long-term benefit of immunotherapy.

Patient summary

To determine the optimal first-line therapy for metastatic bladder cancer patients who are unfit for cisplatin, we compared carboplatin-based chemotherapy versus immunotherapy using real-world data. Survival in the 1st year of treatment was lower with immunotherapy relative to chemotherapy, but for patients surviving beyond the 1st year, immunotherapy was superior.

SUBMITTER: Feld E

PROVIDER: S-EPMC6822167 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Effectiveness of First-line Immune Checkpoint Blockade Versus Carboplatin-based Chemotherapy for Metastatic Urothelial Cancer.

Feld Emily E Harton Joanna J Meropol Neal J NJ Adamson Blythe J S BJS Cohen Aaron A Parikh Ravi B RB Galsky Matthew D MD Narayan Vivek V Christodouleas John J Vaughn David J DJ Hubbard Rebecca A RA Mamtani Ronac R

European urology 20190728 4

<h4>Background</h4>Limited data compare first-line carboplatin-based chemotherapy and immune checkpoint blockade in cisplatin-ineligible metastatic urothelial carcinoma (mUC) patients. The primary evidence guiding treatment decisions was a recent Food and Drug Administration/European Medicines Agency safety alert based on emerging data from two ongoing phase III trials, reporting shorter survival in programmed death-ligand 1 (PD-L1)-negative patients receiving immunotherapy. Final results from t ...[more]

PMID: 31362898

Similar Datasets

Project description:Urothelial carcinoma (UC) is a frequently diagnosed tumor and an important cause of cancer deaths worldwide. Until a few years ago, despite the unquestioned role of platinum-based chemotherapy, therapeutic choices beyond the first line were limited and related to unsatisfactory outcomes. Metastatic UC has always been associated with a poor prognosis, with overall survival only slightly above a year. In the recent past, huge progress has been made in our understanding of the molecular and genomic disease characteristics, to enable stratification of patients in terms of prognosis and treatment responses. Unfortunately, we still do not have the perfect combination of clinical biomarkers to tailor the optimal treatment for each patient, despite making several efforts in this direction. The therapeutic arsenal has been augmented by immune checkpoint inhibitors (ICIs), which nowadays represent the backbone of the second-line setting. Equally revolutionary was the FDA's approval of erdafitinib, a potent fibroblast growth factor receptor (FGFR) inhibitor, the use of which is reserved for patients whose tumor harbors specific FGF pathway alterations. Recently, the therapeutic landscape of metastatic UC has been enhanced by the introduction of novel compounds, consisting of antibody-drug conjugates (ADCs). Enfortumab vedotin is an antibody targeting nectin-4, a cell adhesion molecule highly expressed in UC, conjugated to monomethyl auristatin E (MMAE), a microtubule-disrupting agent. Sacituzumab govitecan is a humanized monoclonal antibody targeting Trop-2, a transmembrane glycoprotein, conjugated to the active metabolite of irinotecan. These two compounds have received accelerated approval by the FDA in patients pretreated with platinum-based chemotherapy and immunotherapy. Several ongoing trials are investigating the role of ICIs combined with chemotherapy, antiangiogenic drugs, or other ICIs, as well as the efficacy of PARP inhibitors and target therapies, hoping to provide information for some important unmet needs. In this review, we aim to evaluate the current potential treatment options after first-line chemotherapy.

Project description:BackgroundGemcitabine with platinum is one of the most important first-line treatments for metastatic urothelial cancer (mUC). However, continuation of platinum agents results in cumulative toxicities, such as nephrotoxicity, ototoxicity, and neurotoxicity, which lead to discontinuation of chemotherapy after 4-6 cycles despite a favorable response in the patients. The strategy of maintenance treatment can give clinical benefit to patients, but there is no consensus about maintenance treatment. The aim of this study was to investigate the clinical impact of the gemcitabine maintenance (GEM-m) in mUC patients who achieve disease control from first-line gemcitabine with platinum agents.MethodsA total of 117 patients who showed response to 4-6 cycles of gemcitabine plus cisplatin or carboplatin as the first-line palliative chemotherapy were reviewed between 2014 to 2018. Patients who were treated with GEM-m received a 1,000 mg/m2 dose of gemcitabine on day 1 and 8 for 3 weeks until disease progression or development of unacceptable toxicity. The patients who are not treated with GEM-m were followed up with regular radiologic evaluation. Statistical analyses were performed using the log-rank test and Cox proportional hazards method.ResultsFifty-eight patients (49.6%) received GEM-m. The median cycle of GEM-m was 4 (range, 1-12). Six patients (10.3%) in the GEM-m group showed an objective response. A median overall survival (OS) of 11.8 months and 9.6 months was observed for the GEM-m and non-GEM-m groups, respectively [HR 0.621; 95% CI, 0.39-0.97; P=0.026]. Additionally, median progression-free survival (PFS) was 4.6 months and 3.3 months in the GEM-m and non-GEM-m groups, respectively [HR 0.612; 95% CI, 0.41-0.91; P=0.009]. Grade 3 or higher neutropenia occurred in 17.2% of patients in the GEM-m and 1.7% in the non-GEM-m group.ConclusionsOur results suggest that GEM-m can be considered in patients who respond to gemcitabine with platinum. Large-scale prospective study should be warranted.

Project description:BackgroundUrothelial carcinoma is a significant health concern in the United States (US), with high mortality and economic burdens. The CheckMate-901 trial showed promising survival benefits for nivolumab combined with gemcitabine and cisplatin followed by nivolumab maintenance therapy (nivolumab-combination) as first-line treatment of unresectable or metastatic urothelial carcinoma (UC), but its cost-effectiveness is unclear.ObjectivesThis study aimed to evaluate the cost-effectiveness of the nivolumab-combination versus standard chemotherapy (gemcitabine-cisplatin) for advanced UC from the perspective of healthcare payers in the US.DesignA model-based pharmacoeconomic evaluation.MethodsBased on the CheckMate-901 study, a three-state Markov model (progression-free, progression, and death) was developed to evaluate the cost-effectiveness of nivolumab-combination versus gemcitabine-cisplatin as a first-line treatment for unresectable or metastatic UC. The model's outputs included quality-adjusted life years (QALYs) and costs and were used to calculate the incremental cost-effectiveness ratio (ICER). Costs included drug prices, adverse event management, and healthcare resource utilization from a US healthcare payer's perspective. State utilities were derived from published literature. One-way sensitivity analysis and probabilistic sensitivity analysis were used to test model robustness. Scenario analyses for drug costs in the UK and Australian health systems were performed.ResultsCompared with gemcitabine-cisplatin, the nivolumab-combination resulted in an additional 0.416 QALYs at an incremental cost of $90,523, yielding an ICER of $217,527 per QALY. Sensitivity analyses indicated significant impacts from the cost of nivolumab maintenance therapy.ConclusionCompared with gemcitabine-cisplatin, nivolumab-combination therapy is not cost-effective for unresectable or metastatic UC at a $100,000 per QALY threshold. High drug prices in the US significantly impact cost-effectiveness, highlighting the need for price negotiations and healthcare policy adjustments to balance innovation incentives and patient affordability.

Project description:PurposePlatinum-based chemotherapy for first-line treatment of metastatic urothelial cancer is typically administered for a fixed duration followed by observation until progression. "Switch maintenance" therapy with PD-1 blockade at the time of chemotherapy cessation may be attractive for mechanistic and pragmatic reasons.Patients and methodsPatients with metastatic urothelial cancer achieving at least stable disease on first-line platinum-based chemotherapy were enrolled. Patients were randomly assigned double-blind 1:1 to switch maintenance pembrolizumab 200 mg intravenously once every 3 weeks versus placebo for up to 24 months. Patients with disease progression on placebo could cross over to pembrolizumab. The primary objective was to determine the progression-free survival. Secondary objectives included determining overall survival as well as treatment outcomes according to PD-L1 combined positive score (CPS).ResultsBetween December 2015 and November 2018, 108 patients were randomly assigned to pembrolizumab (n = 55) or placebo (n = 53). The objective response rate was 23% with pembrolizumab and 10% with placebo. Treatment-emergent grade 3-4 adverse events occurred in 59% receiving pembrolizumab and 38% of patients receiving placebo. Progression-free survival was significantly longer with maintenance pembrolizumab versus placebo (5.4 months [95% CI, 3.1 to 7.3 months] v 3.0 months [95% CI; 2.7 to 5.5 months]; hazard ratio, 0.65; log-rank P = .04; maximum efficiency robust test P = .039). Median overall survival was 22 months (95% CI, 12.9 months to not reached) with pembrolizumab and 18.7 months (95% CI, 11.4 months to not reached) with placebo. There was no significant interaction between PD-L1 CPS ≥ 10 and treatment arm for progression-free survival or overall survival.ConclusionSwitch maintenance pembrolizumab leads to additional objective responses in patients achieving at least stable disease with first-line platinum-based chemotherapy and prolongs progression-free survival in patients with metastatic urothelial cancer.

Project description:BackgroundSintilimab plus chemotherapy significantly prolongs overall survival (OS) for patients with advanced or metastatic oesophageal squamous cell carcinoma (OSCC). However, the cost-effectiveness of this high-priced therapy is currently unknown. We evaluated the cost-effectiveness of sintilimab plus chemotherapy vs chemotherapy alone as fist-line therapy in patients with advanced or metastatic OSCC from the perspective of Chinese healthcare system.MethodsA partitioned survival model consisting of 3 discrete health states was constructed to assess the cost and effectiveness of sintilimab plus chemotherapy vs chemotherapy as first-line treatment of OSCC. Key clinical data in the model came from the ORIENT-15 trial. Costs and utilities were collected from published sources. Life-years, quality-adjusted life-years (QALYs), incremental cost-effectiveness ratio (ICER), incremental net health benefits (INHB), and incremental net monetary benefits (INMB) were calculated for the two treatment strategies. One-way and probabilistic sensitivity analyses were conducted to account for uncertainty and model stability. Additional subgroup and scenario analyses were performed.ResultsTreatment with sintilimab plus chemotherapy provided an additional 0.37 QALYs and an incremental cost of $8,046.58 compared with chemotherapy, which resulted in an ICER of $21,782.24 per QALY gained. One-way sensitivity analysis revealed that the model was most sensitive to utility of progression-free survival (PFS) and the cost of sintilimab. The probabilistic sensitivity analysis indicated that the probability of sintilimab plus chemotherapy being cost-effective was 0.01%, 76.80% and 98.60% at the threshold of 1, 2 or 3 times GDP per capita per QALY, respectively. Subgroup analysis found that all subgroups other than PD-L1 expression combined positive scores < 1 subgroup favored sintilimab plus chemotherapy treatment due to its association with positive INHBs by varying the hazard ratios for OS and PFS. The scenario analyses showed altering the time horizon of the model or fitting survival curves separately did not reverse results of the model.ConclusionSintilimab plus chemotherapy was associated with improved QALYs and an additional cost but was estimated to be cost-effective compared with chemotherapy alone as a first-line treatment for patients with advanced or metastatic OSCC at the commonly adopted willingness-to-pay threshold of 3 times GDP per capita per QALY in China.

Dataset Information

Effectiveness of First-line Immune Checkpoint Blockade Versus Carboplatin-based Chemotherapy for Metastatic Urothelial Cancer.

Background

Objective

Design, setting, and participants

Outcome measurements and statistical analysis

Results and limitations

Conclusions

Patient summary

Publications

Effectiveness of First-line Immune Checkpoint Blockade Versus Carboplatin-based Chemotherapy for Metastatic Urothelial Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets