Dataset Information

Association of prior local therapy and outcomes with programmed-death ligand-1 inhibitors in advanced urothelial cancer.

ABSTRACT:

Objectives

To compare clinical outcomes with programmed-death ligand-1 immune checkpoint inhibitors (ICIs) in patients with advanced urothelial carcinoma (aUC) who have vs have not undergone radical surgery (RS) or radiation therapy (RT) prior to developing metastatic disease.

Patients and methods

We performed a retrospective cohort study collecting clinicopathological, treatment and outcomes data for patients with aUC receiving ICIs across 25 institutions. We compared outcomes (observed response rate [ORR], progression-free survival [PFS], overall survival [OS]) between patients with vs without prior RS, and by type of prior locoregional treatment (RS vs RT vs no locoregional treatment). Patients with de novo advanced disease were excluded. Analysis was stratified by treatment line (first-line and second-line or greater [second-plus line]). Logistic regression was used to compare ORR, while Kaplan-Meier analysis and Cox regression were used for PFS and OS. Multivariable models were adjusted for known prognostic factors.

Results

We included 562 patients (first-line: 342 and second-plus line: 220). There was no difference in outcomes based on prior locoregional treatment among those treated with first-line ICIs. In the second-plus-line setting, prior RS was associated with higher ORR (adjusted odds ratio 2.61, 95% confidence interval [CI]1.19-5.74]), longer OS (adjusted hazard ratio [aHR] 0.61, 95% CI 0.42-0.88) and PFS (aHR 0.63, 95% CI 0.45-0.89) vs no prior RS. This association remained significant when type of prior locoregional treatment (RS and RT) was modelled separately.

Conclusion

Prior RS before developing advanced disease was associated with better outcomes in patients with aUC treated with ICIs in the second-plus-line but not in the first-line setting. While further validation is needed, our findings could have implications for prognostic estimates in clinical discussions and benchmarking for clinical trials. Limitations include the study's retrospective nature, lack of randomization, and possible selection and confounding biases.

SUBMITTER: Makrakis D

PROVIDER: S-EPMC10257152 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Publications

Association of prior local therapy and outcomes with programmed-death ligand-1 inhibitors in advanced urothelial cancer.

Makrakis Dimitrios D Talukder Rafee R Diamantopoulos Leonidas N LN Carril-Ajuria Lucia L Castellano Daniel D De Kouchkovsky Ivan I Koshkin Vadim S VS Park Joseph J JJ Alva Ajjai A Bilen Mehmet A MA Stewart Tyler F TF McKay Rana R RR Santos Victor S VS Agarwal Neeraj N Jain Jayanshu J Zakharia Yousef Y Morales-Barrera Rafael R Devitt Michael E ME Grant Michael M Lythgoe Mark P MP Pinato David J DJ Nelson Ariel A Hoimes Christopher J CJ Shreck Evan E Gartrell Benjamin A BA Sankin Alex A Tripathi Abhishek A Zakopoulou Roubini R Bamias Aristotelis A Murgic Jure J Fröbe Ana A Rodriguez-Vida Alejo A Drakaki Alexandra A Liu Sandy S Kumar Vivek V Di Lorenzo Giuseppe G Joshi Monika M Isaacsson-Velho Pedro P Buznego Lucia Alonso LA Duran Ignacio I Moses Marcus M Barata Pedro P Sonpavde Guru G Yu Evan Y EY Wright Jonathan L JL Grivas Petros P Khaki Ali Raza AR

BJU international 20211025 5

<h4>Objectives</h4>To compare clinical outcomes with programmed-death ligand-1 immune checkpoint inhibitors (ICIs) in patients with advanced urothelial carcinoma (aUC) who have vs have not undergone radical surgery (RS) or radiation therapy (RT) prior to developing metastatic disease.<h4>Patients and methods</h4>We performed a retrospective cohort study collecting clinicopathological, treatment and outcomes data for patients with aUC receiving ICIs across 25 institutions. We compared outcomes (o ...[more]

PMID: 34597472

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Project description:IntroductionProgrammed cell death-1/programmed cell death ligand-1 (PD-1/PDL-1) inhibitors are the newest class of approved drugs for advanced urothelial cancer (AdUC). This review aims to collate the evidence for their efficacy and safety in various treatment settings.MethodsExtensive search of databases was performed (updated May 2018) and the protocol was registered on PROSPERO (CRD42017081568). The review was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis statement. STATA (v 12) and Revman 5.3.5 were used for data analysis.ResultsTen nonrandomized, open-label clinical trials were included in this review. PD-1/PD-L1 inhibitors were used as second-line, stand-alone in eight trials and as first-line in cisplatin-ineligible in two trials. Heterogeneity was observed for study design, PDL-1 testing methods, cutoff criterias used and translational markers evaluated. The pooled objective response rate (ORR) was 18.2% (95% confidence interval [CI] 15.1-21.2, n = 1785) with PD-1/PDL-1 inhibitors in second-line settings as compared to 12.6% (95% CI 10.3-14.9, n = 736) with second-line chemotherapy and 23.7% (95% CI 19.9-27.4, n = 489) with PD-1/PDL-1 inhibitors as first-line therapy in cisplatin-ineligible patients. The median progression-free survival and overall survival was similar with PD-1/PD-L1 inhibitors in both second- and first-line treatment settings (1.5-2.9 vs. 2.0-2.7 months and 7.9-18.2 vs. 15.9 months) and second-line chemotherapy (3.3-4.0 months and 7.4-8 months). Odds of achieving ORR was 0.10 (95% CI 0.03-0.31, n = 229) in the second-line, stand-alone setting with a combined positive score (CPS) cutoff of 25% and was 0.34 (95% CI 0.19-0.62, n = 265) with a CPS cut-off of 10% in first-line setting in the cisplatin-ineligible.ConclusionsPD-1/PDL-1 inhibitors appear to be promising in the treatment of AdUC and CPS may be a potentially reliable biomarker for predicting response but needs validation. Caution needs to be exercised until more data are available on imAEs and further studies are required to prove their worth as the standard of care.

Project description:PurposeLocally advanced or metastatic urothelial carcinoma is an incurable disease with limited treatment options, especially for patients who were previously treated with platinum and anti-programmed death 1 or anti-programmed death ligand 1 (PD-1/L1) therapy. Enfortumab vedotin is an antibody-drug conjugate that targets Nectin-4, which is highly expressed in urothelial carcinoma.MethodsEV-201 is a global, phase II, single-arm study of enfortumab vedotin 1.25 mg/kg (intravenously on days 1, 8, and 15 of every 28-day cycle) in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum chemotherapy and anti-PD-1/L1 therapy. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review. Key secondary end points were duration of response, progression-free survival, overall survival, safety, and tolerability.ResultsEnfortumab vedotin was administered to 125 patients with metastatic urothelial carcinoma. Median follow-up was 10.2 months (range, 0.5 to 16.5 months). Confirmed objective response rate was 44% (95% CI, 35.1% to 53.2%), including 12% complete responses. Similar responses were observed in prespecified subgroups, such as those patients with liver metastases and those with no response to prior anti-PD-1/L1 therapy. Median duration of response was 7.6 months (range, 0.95 to 11.30+ months). The most common treatment-related adverse events were fatigue (50%), any peripheral neuropathy (50%), alopecia (49%), any rash (48%), decreased appetite (44%), and dysgeusia (40%). No single treatment-related adverse events grade 3 or greater occurred in 10% or more of patients.ConclusionEnfortumab vedotin demonstrated a clinically meaningful response rate with a manageable and tolerable safety profile in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum and anti-PD-1/L1 therapies.

Project description:Take Home Message This retrospective study found some evidence of potential lower response rates and shortened overall survival following anti–programmed death-(ligand) 1 therapy in patients with metastatic urothelial carcinoma with prespecified fibroblast growth factor receptor alterations (FGFRa) than in those without FGFRa who received prior immunotherapy between May 2018 and July 2019. Background Clinical outcomes of anti–programmed death‑(ligand) 1 (anti–PD-[L]1) therapy in patients with locally advanced or metastatic urothelial carcinoma (mUC) and fibroblast growth factor receptor alterations (FGFRa+) remain unclear; recent studies have reported either comparable or poorer outcomes versus patients without FGFR alterations (FGFRa–). Objective To analyze the outcomes of patients with mUC and any FGFRa (mutations or fusions) who received anti–PD-(L)1 therapy. Design, setting, and participants In this noninterventional, retrospective, multicenter study, clinical practice data were collected from FGFRa+/– patients who received prior immunotherapy between May 2018 and July 2019. Outcome measurements and statistical analysis Investigator‑determined overall response rate (ORR), disease control rate (DCR), and overall survival (OS) were assessed in multivariate and unadjusted analyses. Results and limitations Ninety-four patients (66% men; median age, 63 yr) with mUC and known FGFR status were included; 38 (40%) were FGFRa+ and 56 (60%) were FGFRa–. In FGFRa+ versus FGFRa– patients who received any line of anti–PD-(L)1 therapy (n = 92), ORR, DCR, and OS were 16% versus 26%, 29% versus 52% (relative risk: 1.14 [95% confidence interval {CI}, 0.92–1.40]; p = 0.3), and 8.57 versus 13.2 mo (hazard ratio [HR]: 1.33 [95% CI, 0.77–2.30]; p = 0.3), respectively. A multivariate analysis provided some evidence supporting shorter OS in FGFRa+ versus FGFRa– (any line of anti–PD-L[1] therapy; HR: 1.81 [95% CI, 0.99–3.31]; p = 0.054). Limitations include this study’s retrospective nature and a potential selection bias from small sample size. Conclusions Some evidence of lower response rates and shortened OS following anti–PD-(L)1 therapy was observed in FGFRa+ patients. The phase 3 THOR study (NCT03390504) will prospectively compare FGFRa+ patients with advanced mUC treated with erdafitinib versus pembrolizumab. Patient summary Patients with metastatic urothelial carcinoma and prespecified fibroblast growth factor receptor alterations (FGFRa) potentially have worse clinical outcomes when treated with anti–PD-(L)1 therapy than those without FGFRa.

Dataset Information

Association of prior local therapy and outcomes with programmed-death ligand-1 inhibitors in advanced urothelial cancer.

Objectives

Patients and methods

Results

Conclusion

Publications

Association of prior local therapy and outcomes with programmed-death ligand-1 inhibitors in advanced urothelial cancer.

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