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.

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.

EV-201: Results of enfortumab vedotin monotherapy for locally advanced or metastatic urothelial cancer previously treated with platinum and immune checkpoint inhibitors.

2019 ◽  
Vol 37 (18_suppl) ◽  
pp. 4505-4505 ◽  
Author(s):  
Daniel Peter Petrylak ◽  
Arjun Vasant Balar ◽  
Peter H. O'Donnell ◽  
Bradley Alexander McGregor ◽  
Elisabeth I. Heath ◽  
...  
Keyword(s):  
Urothelial Cancer ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Locally Advanced ◽  
Unmet Need ◽  
Antibody Drug Conjugate ◽  
Open Label ◽  
Metastatic Urothelial Cancer ◽  
Duration Of Response ◽  
Previously Treated

4505 Background: Locally advanced or metastatic urothelial cancer (la/mUC) remains a lethal disease with limited treatment options for patients (pts) who progress on or after platinum and/or checkpoint inhibitor (CPI). Enfortumab vedotin (EV) is an antibody-drug conjugate targeting Nectin-4, which is highly expressed in UC. EV-201 is a pivotal, single-arm, two-cohort study of EV in la/mUC patients with prior CPI and platinum-containing chemotherapy (Cohort 1) or a CPI and no prior chemotherapy (Cohort 2). Here, we present preliminary data from Cohort 1. Methods: Pts in this open-label, multicenter study received 1.25 mg/kg EV on Days 1, 8, and 15 of each 28-day cycle. The primary endpoint was confirmed ORR per RECIST 1.1 by blinded independent central review. Secondary endpoints are duration of response, PFS, OS, safety/tolerability. Results: Between Oct 2017 and Jul 2018, EV-201 enrolled 128 pts in Cohort 1 (la/mUC pts previously treated with platinum and a CPI), 125 of whom were treated with EV (70% male; median age 69 y [range 40–84 y]; 34% upper tract; a median of 2 prior systemic therapies). As of 03 Jan 2019, the confirmed ORR was 42% (95% CI: 33.6%–51.6%), with 9% CR. The ORR in CPI non-responders was 38% (95% CI: 27.3%–49.2%), and 36% (95% CI: 22.9%–50.8%) in pts with liver metastases (LM). Most common treatment-related AEs, as determined by investigators, included fatigue (50%), alopecia (48%), and decreased appetite (41%). Treatment-related AEs of interest include any rash (48% all grade, 11% ≥ G3) and any peripheral neuropathy (50% all grade, 3% ≥ G3). One death was reported as treatment related by the investigator (interstitial lung disease), but was confounded by a suspected pulmonary infection. Conclusions: Preliminary results from this EV pivotal study demonstrated a clinically meaningful ORR, consistent with the phase 1 trial, in la/mUC pts with prior platinum and CPI, including LM pts, where there is a high unmet need. EV was well tolerated with a manageable safety profile in these pts. Updated data, including duration of response, PFS, and OS will be presented. Clinical trial information: NCT03219333.

scholarly journals Targeted therapies for advanced bladder cancer: new strategies with FGFR inhibitors

2019 ◽  
Vol 11 ◽  
pp. 175883591989028 ◽  
Author(s):  
Chiara Casadei ◽  
Nazli Dizman ◽  
Giuseppe Schepisi ◽  
Maria Concetta Cursano ◽  
Umberto Basso ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Checkpoint Inhibitors ◽  
Growth Factor Receptor ◽  
Clinical Approach ◽  
Antitumor Effects ◽  
Development Of Resistance ◽  
Platinum Based Chemotherapy ◽  
Accelerated Approval ◽  
Combination Regimens ◽  
New Strategies

Inhibitors of fibroblast growth factor receptor (FGFR) represent an outstanding treatment approach for selected patients with urothelial cancer (UC). These agents are changing the clinical approach to a subgroup of UC, the luminal-papillary subtype, characterized by FGFR mutations, fusions, or amplification. In this review, we provide an overview of the results of recent clinical trials on FGFR tyrosine kinase inhibitors (TKIs) currently in clinical development for the treatment of UC: erdafitinib, rogaratinib, infigratinib, and the monoclonal antibody vofatamab. The Food and Drug Administration recently granted accelerated approval to erdafitinib for patients with advanced UC with alterations of FGFR2 or FGFR3 after progression on platinum-based chemotherapy. We also look at future therapeutic options of combination regimens with immune-checkpoint inhibitors as strategies for improving the antitumor effects of this class of drug, and for preventing or delaying the development of resistance.

scholarly journals Current options and future directions of systemic therapy for advanced biliary tract cancer

2021 ◽  
Vol 2 (5) ◽  
Author(s):  
Maria Giuseppina Prete ◽  
Antonella Cammarota ◽  
Antonio D'Alessio ◽  
Valentina Zanuso ◽  
Lorenza Rimassa
Keyword(s):  
Growth Factor ◽  
Biliary Tract ◽  
Checkpoint Inhibitors ◽  
Growth Factor Receptor ◽  
Biliary Tree ◽  
Driver Mutations ◽  
Anatomical Location ◽  
Braf Mutations ◽  
Future Directions ◽  
Platinum Based Chemotherapy

Biliary tract cancers (BTCs) are aggressive tumors arising from different portions of the biliary tree and classified according to the anatomical location in intrahepatic (i) cholangiocarcinoma (CCA, iCCA), perihilar CCA (pCCA), and distal CCA (dCCA), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC). Due to their silent behavior, BTCs are frequently diagnosed at advanced stages when the prognosis is poor. The available chemotherapeutic options are palliative and unfortunately, most patients will die from their disease between 6 and 18 months from diagnosis. However, over the last decade, amounting interest has been posed on the genomic landscape of BTCs and deep-sequencing studies have identified different potentially actionable driver mutations. Hence, the promising results of the early phase clinical studies with targeted agents against isocitrate dehydrogenase (IDH) 1 mutation or fibroblast growth factor (FGF) receptor(FGFR) 2 aberrations inintrahepatic tumors, and other agents against humanepidermal growth factor receptor (HER) 2 overexpression/mutations, neurotrophic tyrosine receptor kinase (NTRK) fusions or B-type Raf kinase (BRAF) mutations across different subtypes of BTCs, have paved the way for a “precision medicine” strategy for BTCs. Moreover, despite the modest results when used as monotherapy, beyond microsatellite instability-high (MSI-H) tumors, immune checkpoint inhibitors are being evaluated in combination with platinum-based chemotherapy, possibly further expanding the therapeutic landscape of advanced BTCs. This review aims to provide an overview of the approved systemic therapies, the promising results, and the ongoing studies to explore the current and future directions of advanced BTC systemic treatment.

Effect of EGFR inhibition with cetuximab on the efficacy of paclitaxel in previously treated metastatic urothelial cancer.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 243-243 ◽  
Author(s):  
Y. Wong ◽  
S. Litwin ◽  
E. R. Plimack ◽  
D. J. Vaughn ◽  
W. Song ◽  
...  
Keyword(s):  
Urothelial Cancer ◽  
Growth Factor Receptor ◽  
Salvage Chemotherapy ◽  
Egfr Inhibition ◽  
Type 1 Error ◽  
Metastatic Urothelial Cancer ◽  
Platinum Based Chemotherapy ◽  
Previously Treated ◽  
Number Of Cycles ◽  
Visceral Disease

243 Background: The benefit of salvage chemotherapy such as weekly paclitaxel (TAX) is modest in metastatic (met) urothelial ca, with median TTP of ≤3 months and ORR of 10% (95% CI 4-18% [combined results, Vaughn 2002; Joly, 2009]). Cetuximab (CET) is a monoclonal antibody against the epidermal growth factor receptor (EGFR). High-grade urothelial cancer overexpress EGFR. We conducted a multicenter randomized, noncomparative phase II study to measure the efficacy of CET ± TAX in patients (pts) with previously treated met urothelial cancer. Methods: Pts with met urothelial cancer who received one line of chemotherapy in the adjuvant, neoadjvuant, or met setting were enrolled. Pts were randomized to CET 250mg/m2 (after 400 mg/m2 load) ± TAX 80 mg/m2 weekly. A cycle was 4 weeks (wks). Response (RECIST) was assessed by imaging every 8 wks. We used early progression to assess futility (Litwin Stats Med 2007). Either arm would close if 7 of the initial 15 pts in that arm progressed at the first disease evaluation. Either arm would be considered promising if ≥9/28 patients had PFS>16 wks (90.4% power to detect an improvement in Median [Med] PFS from 8 to 16 wks with a 7.1% type 1 error). Results: We enrolled 39 evaluable pts (30 male). Median age was 69 years (range 49-79). All pts received prior platinum-based chemotherapy. CET arm closed after 9 of the first 11 pts progressed by 8 wks (ASCO GU 2009). CET-TAX arm completed full accrual (28 pts), of which 11 had visceral disease and 13 received chemo for met disease. 10/28 pts had PFS>16 wks. Overall RR was 28.5%, (8/28 pts, 95% CI 13-49%) (2 CR, 6PR). 4 additional pts had unconfirmed PR. 2 pts have maintained PR 3 and 4 months after discontinuing CET-TAX. Med PFS for the CET-TAX was 115 days (16 weeks)(95% CI 58-174 days). Med PFS for pts with visceral disease was 84 days (95%CI 50-NR). Med PFS for pts who received prior chemo for met disease was 142 days (95% 58-NR). Med number of cycles for the CET-TAX was 3 (range 0-25). Grade 3 AEs occurring in more than 2 pts were rash (5), fatigue (4), anemia (4), low magnesium (3). Conclusions: EGFR inhibition with CET appears to augment the antitumor activity of TAX in pts with previously treated urothelial cancers. The CET-TAX combination merits further study to establish its role in treatment of urothelial cancers. [Table: see text]

scholarly journals Double-Blind, Randomized Trial of Docetaxel Plus Vandetanib Versus Docetaxel Plus Placebo in Platinum-Pretreated Metastatic Urothelial Cancer

2012 ◽  
Vol 30 (5) ◽  
pp. 507-512 ◽  
Author(s):  
Toni K. Choueiri ◽  
Robert W. Ross ◽  
Susanna Jacobus ◽  
Ulka Vaishampayan ◽  
Evan Y. Yu ◽  
...  
Keyword(s):  
Growth Factor ◽  
Urothelial Cancer ◽  
Kinase Inhibitor ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Double Blind ◽  
Metastatic Urothelial Cancer ◽  
Platinum Based Chemotherapy

Purpose Vandetanib is an oral once-daily tyrosine kinase inhibitor with activity against vascular endothelial growth factor receptor 2 and epidermal growth factor receptor. Vandetanib in combination with docetaxel was assessed in patients with advanced urothelial cancer (UC) who progressed on prior platinum-based chemotherapy. Patients and Methods The primary objective was to determine whether vandetanib 100 mg plus docetaxel 75 mg/m2 intravenously every 21 days prolonged progression-free survival (PFS) versus placebo plus docetaxel. The study was designed to detect a 60% improvement in median PFS with 80% power and one-sided α at 5%. Patients receiving docetaxel plus placebo had the option to cross over to single-agent vandetanib at progression. Overall survival (OS), overall response rate (ORR), and safety were secondary objectives. Results In all, 142 patients were randomly assigned and received at least one dose of therapy. Median PFS was 2.56 months for the docetaxel plus vandetanib arm versus 1.58 months for the docetaxel plus placebo arm, and the hazard ratio for PFS was 1.02 (95% CI, 0.69 to 1.49; P = .9). ORR and OS were not different between both arms. Grade 3 or higher toxicities were more commonly seen in the docetaxel plus vandetanib arm and included rash/photosensitivity (11% v 0%) and diarrhea (7% v 0%). Among 37 patients who crossed over to single-agent vandetanib, ORR was 3% and OS was 5.2 months. Conclusion In this platinum-pretreated population of advanced UC, the addition of vandetanib to docetaxel did not result in a significant improvement in PFS, ORR, or OS. The toxicity of vandetanib plus docetaxel was greater than that for vendetanib plus placebo. Single-agent vandetanib activity was minimal.

EV-103: Enfortumab vedotin plus pembrolizumab and/or chemotherapy for locally advanced or metastatic urothelial cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS4593-TPS4593 ◽  
Author(s):  
Christopher J. Hoimes ◽  
Jonathan E. Rosenberg ◽  
Daniel Peter Petrylak ◽  
Anne-Sophie Carret ◽  
Amal Melhem-Bertrandt ◽  
...  
Keyword(s):  
Urothelial Cancer ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Locally Advanced ◽  
Primary Objective ◽  
Combination Therapies ◽  
Antibody Drug Conjugate ◽  
Metastatic Urothelial Cancer ◽  
Duration Of Response ◽  
Combination Approach

TPS4593 Background: PD-(L)1-targeted immune checkpoint inhibitors (CPIs), such as pembrolizumab (P), are approved for patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC) who progress after platinum, are ineligible for first-line (1L) cisplatin (PD-L1 positive), or are ineligible for 1L platinum. The ORR for CPI in all treated pts is ~25%, and a combination approach may provide additional benefit. Enfortumab vedotin (EV), an investigational antibody-drug conjugate, delivers the microtubule-disrupting agent monomethyl auristatin E to cells expressing Nectin-4, found in 97% of mUC pt samples (Petrylak ASCO 2017). In a phase 1 study (NCT02091999), EV (1.25 mg/kg) was generally well tolerated with a confirmed ORR of 43% in 112 mUC pts (Rosenberg ASCO-GU 2019). These encouraging results, with the potential for an enhanced immune response, suggest that EV+P may improve response rates and extend response durability. Methods: EV-103, a phase 1b trial for non–resectable la/mUC pts with no prior CPI, added an additional 4 cohorts (Parts 2 and 3) in an Oct 2018 amendment. It is now expected to enroll ~159 pts. Dose escalation pts (EV+P, 1L or 2L) must be ineligible for 1L cisplatin-based chemotherapy or have disease progression during/following treatment with ≥1 platinum-containing regimen. Dose expansion (Part 1) will evaluate EV+P in 1L (Cohort A) and 2L settings (Optional Cohort B). Part 2 will evaluate 1L EV+cisplatin (Cohort D), 1L EV+carboplatin (Cohort E), and 1L or 2L EV+gemcitabine (Optional Cohort F). Part 3 (Cohort G) will evaluate 1L EV+P+cisplatin or carboplatin, depending on pts cisplatin-eligibility. In all cohorts, pts receive EV on Days 1 and 8 of each 3-week cycle. In combination therapies, pts receive P, cisplatin, and carboplatin on Day 1 or gemcitabine on Days 1 and 8 of each cycle. The primary objective is to assess the safety/tolerability of EV+P and/or chemotherapy. Secondary objectives are establishing EV recommended dose for combination therapies, assessing ORR per RECIST for all cohorts and per iRECIST for therapies with pembrolizumab, as well as assessing disease control rate, duration of response, PFS, OS, PK, and biomarkers. The study opened Oct 2017. Clinical trial information: NCT03288545.

scholarly journals Atezolizumab in locally advanced or metastatic urothelial cancer: a pooled analysis from the Spanish patients of the IMvigor 210 cohort 2 and 211 studies

2020 ◽  
Author(s):  
M. Sotelo ◽  
T. Alonso-Gordoa ◽  
P. Gajate ◽  
E. Gallardo ◽  
R. Morales-Barrera ◽  
...  
Keyword(s):  
Median Duration ◽  
Urothelial Cancer ◽  
Objective Response ◽  
Locally Advanced ◽  
Survival Rates ◽  
Pooled Analysis ◽  
Metastatic Urothelial Cancer ◽  
Platinum Based Chemotherapy ◽  
Geographical Regions ◽  
Duration Of Response

Abstract Background The studies IMvigor 210 cohort 2 and IMvigor211 evaluated the efficacy of atezolizumab in patients with locally advanced or metastatic urothelial cancer (mUC) upon progression to platinum-based chemotherapy worldwide. Yet, the real impact of this drug in specific geographical regions is unknown. Materials and methods We combined individual-level data from the 131 patients recruited in Spain from IMvigor210 cohort 2 and IMvigor211 in a pooled analysis. Efficacy and safety outcomes were assessed in the overall study population and according to PD-L1 expression on tumour-infiltrating immune cells. Results Full data were available for 127 patients; 74 (58%) received atezolizumab and 53 (42%) chemotherapy. Atezolizumab patients had a numerically superior median overall survival although not reaching statistical significance (9.2 months vs 7.7 months). No statistically significant differences between arms were observed in overall response rates (20.3% vs 37.0%) or progression-free survival (2.1 months vs 5.3 months). Nonetheless, median duration of response was superior for the immunotherapy arm (non-reached vs 6.4 months; p = 0.005). Additionally, among the responders, the 12-month survival rates seemed to favour atezolizumab (66.7% vs 19.9%). When efficacy was analyzed based on PD-L1 expression status, no significant differences were found. Treatment-related adverse events of any grade occurred more frequently in the chemotherapy arm [46/57 (81%) vs 44/74 (59%)]. Conclusion Patients who achieved an objective response on atezolizumab presented a longer median duration of response and numerically superior 12 month survival rates when compared with chemotherapy responders along with a more favorable safety profile. PD-L1 expression did not discriminate patients who might benefit from atezolizumab.

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