scholarly journals Biomarkers for therapy selection in metastatic urothelial cancer

2022 ◽  
Author(s):  
Tomi Jun ◽  
Jonathan Anker ◽  
Matthew D. Galsky
Keyword(s):  
Recent Progress ◽  
Urothelial Cancer ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Predictive Biomarkers ◽  
Treatment Selection ◽  
Optimal Sequence ◽  
Programmed Death ◽  
Metastatic Urothelial Cancer ◽  
Treatment Paradigm

The treatment of metastatic urothelial cancer (mUC) has been transformed by recent progress in clinical trials and drug development. There are now three therapeutic classes with proven benefits in mUC: chemotherapy, immunotherapy, and targeted therapy. The optimal sequence and combination of these classes remain to be defined. Biomarker development is essential to guide treatment selection at each therapeutic juncture. Two biomarkers, programmed death-ligand 1 expression and fibroblast growth factor receptor alterations, have been incorporated into the mUC treatment paradigm thus far. This review discusses predictive biomarkers in development and their potential to influence mUC treatment selection moving forward.

Fibroblast growth factor receptor status and response to immune checkpoint inhibition in metastatic urothelial cancer.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 458-458 ◽  
Author(s):  
Tracy L Rose ◽  
Michele C Hayward ◽  
Ashley H Salazar ◽  
Patrick Eulitt ◽  
Katrina McGinty ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Immune Checkpoint ◽  
Urothelial Cancer ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Response Rates ◽  
Fibroblast Growth ◽  
Metastatic Urothelial Cancer ◽  
Platinum Based Chemotherapy

458 Background: Fibroblast growth factor receptor (FGFR) inhibitors are a promising new targeted therapy for patients with metastatic urothelial cancer (UC) and FGFR alterations. FGFR-altered tumors are more likely to be of the luminal molecular subtype, which is less immune infiltrated and may be less likely to respond to immune checkpoint inhibitors (ICP). Methods: Metastatic UC patients at the University of North Carolina who underwent targeted exon sequencing (any CLIA-certified platform) and were treated with ICP since 2014 were identified. Patients with any FGFR alteration were compared to patients without alterations (including mutations, fusions, and amplifications in FGFR1-4). Overall response rates (ORR) to ICP were assessed by a radiologist (K.M.) per RECIST 1.1 and compared between FGFR-altered and unaltered tumors using Fisher’s exact tests. Patients who died prior to radiologic assessment were considered non-responders. Results: 66 patients (median age 70, 65% male, 76% white, 21% black) were identified. Most patients (74%) had received prior platinum-based chemotherapy, and 13% had received 2 or more prior lines of therapy. At the time of initiation of ICP, 32% of patients had a hemoglobin < 10, 33% had liver metastases, and 72% had a performance status > 0. Fifteen (22%) patients had FGFR alterations. The ORR for all patients was 15%, with ORR of 13% in FGFR-altered patients compared with 16% in unaltered patients (p = 1.0). No patients (0/9, 0%) with known pathogenic mutations in FGFR3 responded to ICP compared to 10/57 (18%) of patients without these alterations (p = 0.33). 46% of FGFR-altered patients who stopped ICP due to progression received subsequent therapy. Conclusions: Response rates to ICP are low and there was no difference in ORR between FGFR-altered and unaltered patients. While no patient with pathogenic FGFR3 mutations responded to ICP in our cohort, this difference did not reach statistical significance. Given low response rates overall, some FGFR-altered patients may benefit from treatment with FGFR inhibitors prior to ICP. Analysis of larger cohorts of patients as well as patients from clinical trials and more in-depth molecular profiling may add further clarity.

Responses to chemotherapy in patients with metastatic urothelial cancer (MUC) after frontline immunotherapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16004-e16004 ◽  
Author(s):  
Bernadett Szabados ◽  
Michiel Simon Van Der Heijden ◽  
Alfonso Gomez De Liano Lista ◽  
Yen Zhi Tang ◽  
Thomas Powles
Keyword(s):  
Urothelial Cancer ◽  
Chemotherapy Regimen ◽  
Objective Response ◽  
Front Line ◽  
Optimal Sequence ◽  
Kaplan Meier ◽  
Retrospective Audit ◽  
Metastatic Urothelial Cancer ◽  
Median Change ◽  
Line Chemotherapy

e16004 Background: The effect of prior immune checkpoint inhibition therapy (CI) on the efficacy of subsequent chemotherapy is largely unknown in MUC. The identification of the optimal sequence of chemotherapy and IO is yet to be determined, but may influence outcomes. Methods: A retrospective audit and comparison of patients who progressed after first and second line CI and received subsequent standard chemotherapy was performed. Date was collected across a broad spectrum of CI. We report on patient’s characteristics and response rates of 28 sequential patients collected from two institutions who received chemotherapy after CI. Patients were separated into 2 cohorts. Cohort A had not previously received chemotherapy (n = 14), cohort B had previously received at least 1 chemotherapy regimen (n = 14). Central radiology review was performed. We assessed objective response rate by RECIST v 1.1. Kaplan Meier method was used. Results: Median age for the whole cohort was 64 yrs (45-80). ECOG was 0/1 in 89,3% and 2 in 10,7% at the time of starting chemotherapy. The commonest chemotherapy regimen in cohort A and B were carboplatin-gemcitabine (71%) and carboplatin paclitaxel (50%) respectively. 75% of the patients were intermediate risk group. In Cohort A 63% responded to chemotherapy whereas in cohort B only 3 patients showed response. The median change in target lesions in the front line immunotherapy cohort was -60% (-81 to +1%). Both patients who responded to 2nd line chemotherapy after CI had a long interval between first and 2nd line chemotherapy (9-24 months). Conclusions: Chemotherapy maintains its efficacy after front line CI with deep responses. Although numbers are modest, results strongly suggest patients should be offered chemotherapy in this setting.

scholarly journals PIVOT-10: Phase II study of bempegaldesleukin plus nivolumab in cisplatin-ineligible advanced urothelial cancer

2020 ◽  
Author(s):  
Robert A Huddart ◽  
Arlene O Siefker-Radtke ◽  
Arjun V Balar ◽  
Mehmet A Bilen ◽  
Thomas Powles ◽  
...  
Keyword(s):  
Phase Ii ◽  
Urothelial Cancer ◽  
Objective Response ◽  
Locally Advanced ◽  
Response Rates ◽  
Complete Response ◽  
First Line ◽  
First Line Therapy ◽  
Programmed Death ◽  
Metastatic Urothelial Cancer

The choice of first-line therapy for patients with metastatic urothelial cancer (mUC) is based on cisplatin-eligibility and programmed death-ligand 1 (PD-L1) status. For patients with mUC who are ineligible for cisplatin and with low PD-L1 expression, chemotherapy-based regimens are the only approved first-line option. In a Phase I/II trial of the chemotherapy-free regimen, bempegaldesleukin (BEMPEG; NKTR-214) plus nivolumab, patients with locally advanced or mUC experienced tumor responses regardless of baseline PD-L1 expression (objective response rates: 50 and 45% in patients with PD-L1-positive and -negative tumors, respectively). The Phase II PIVOT-10 study (NCT03785925), evaluates efficacy and safety of first-line BEMPEG plus nivolumab in cisplatin-ineligible patients with locally advanced or mUC. Most patients will have low PD-L1 expression. Primary end point: objective response rates (including complete response).

Clinical-pathological characterization and outcomes of metastatic urothelial cancer in Latin America: Retrospective and translational multicenter database (LACOG 1518).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS497-TPS497
Author(s):  
Vinicius Carrera Souza ◽  
Murilo Luz ◽  
Diogo Assed Bastos ◽  
Marcelo Roberto Pereira Freitas ◽  
Breno Dauster Pereira E Silva ◽  
...  
Keyword(s):  
Latin America ◽  
Translational Research ◽  
Urothelial Cancer ◽  
Growth Factor Receptor ◽  
Current Standard ◽  
Optimal Care ◽  
Best Response ◽  
Metastatic Urothelial Cancer ◽  
Advanced Urothelial Cancer ◽  
Line Of Therapy

TPS497 Background: There is lack of high-quality and comprehensive data on advanced urothelial cancer in Latin America. Pathological and clinical outcomes information of this cancer can help the scientific community to understand the current standard of treatment and identify possible gaps for optimal care. Very few translational studies were performed in advanced urothelial cancer in developing countries describing the prevalence of key biomarkers for targeted agents and immunotherapy. Methods: LACOG 1518 is a large multi-institutional retrospective study that will collect information about sociodemographic data, treatment and outcome of patients diagnosed with recurrent/ metastatic urothelial cancer in Latin America between January 2016 and December 2019. Socio-demographic characteristics, clinical-pathological features, treatment patterns and outcomes will be extracted from medical charts. Tumor tissue will be collected for fibroblast growth factor receptor (FGFR) gene mutation or fusion test in a central laboratory. A biorepository will be built for future translational research including PD-L1 test and next generation sequencing. Primary endpoint consists on characterize demographic, socioeconomic factors, medical and oncological history of patients diagnosed with recurrent/metastatic urothelial cancer. This study aim to describe treatment sequence, duration, best response and progression time in each line of therapy as well as survival at 1 and 2 years. Translational research endpoints are biomarkers prevalence and association with treatment responses and outcomes.

scholarly journals Enfortumab Vedotin in urothelial cancer

2020 ◽  
Vol 12 ◽  
pp. 175628722098019
Author(s):  
Marie Alt ◽  
Carlos Stecca ◽  
Swanee Tobin ◽  
Di Maria Jiang ◽  
Srikala S. Sridhar
Keyword(s):  
Urothelial Cancer ◽  
Checkpoint Inhibitors ◽  
Growth Factor Receptor ◽  
Antibody Drug Conjugate ◽  
Future Directions ◽  
Combination Strategies ◽  
Fda Approval ◽  
Metastatic Urothelial Cancer ◽  
Platinum Based Chemotherapy ◽  
Accelerated Approval

The treatment landscape for metastatic urothelial cancer (mUC) beyond first-line platinum-based chemotherapy has changed significantly over the last 5 years with the recent approvals of the immune checkpoint inhibitors (ICIs), fibroblast growth factor receptor (FGFR) inhibitors and most recently Enfortumab Vedotin (EV). EV is a novel antibody–drug conjugate (ADC), that delivers monomethyl auristatin E (MMAE), a microtubule-disrupting agent, inside cells harboring the cell surface nectin-4 receptor. In mUC, EV has shown encouraging response rates and received accelerated approval from the Food and Drug Administration (FDA) in December 2019 in the post-platinum and ICI setting. EV is generally well tolerated, with the main toxicities being neuropathy, skin rash, alopecia and fatigue. Notably EV can also be administered to patients with renal dysfunction, which is commonly a concern in this patient population. EV is now being tested in combination strategies and in earlier disease settings in urothelial cancers. In this review, we will discuss its mechanism of action, clinical trials leading to FDA approval as well as ongoing trials and future directions.

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