Erdafitinib as a Novel and Advanced Treatment Strategy of Metastatic Urothelial Carcinoma

2021 ◽  
Vol 21 ◽  
Author(s):  
Parveen Bansal ◽  
Deepak K. Dwivedi ◽  
Deepa Hatwal ◽  
Priyanka Sharma ◽  
Vikas Gupta ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
First Line ◽  
The Usa ◽  
Metastatic Urothelial Carcinoma ◽  
In The Beginning ◽  
Platinum Chemotherapy ◽  
Common Malignancy ◽  
Fgfr Inhibition

: Urothelial carcinoma has become the ninth most common malignancy in the world. Since 1980s, diverse studies and treatment methods came out with their possible effects along with certain limitations. Initially, platinum chemotherapy was considered as first line treatment of the disease. Although it was proved to be effective in the beginning yet most number of cases reported the reoccurrence of the disease. Furthermore, aberrant ligand-dependent and constitutive ligandindependent fibroblast growth factor receptor (FGFR) signalling has been reported in large number of solid tumours including urothelial carcinoma that became the basis for FGFR inhibition for the treatment of the disease. Erdafitinib is a pan-FGFR inhibitor that was recently approved in the USA for the treatment of locally advanced or metastatic FGFR3 or FGFR2 urothelial carcinoma. The drug is also being investigated as a treatment for other cancers including cholangiocarcinoma, liver cancer, non-small cell lung cancer, prostate cancer, lymphoma cancer and oesophageal cancer. This article summarizes the various treatments evolved for bladder cancer till now, brief description of biology of FGFR inhibition, clinical pharmacology and various clinical trials of erdafitinib.

Study EV-103: Preliminary durability results of enfortumab vedotin plus pembrolizumab for locally advanced or metastatic urothelial carcinoma.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 441-441 ◽  
Author(s):  
Jonathan E. Rosenberg ◽  
Thomas W. Flaig ◽  
Terence W. Friedlander ◽  
Matthew I. Milowsky ◽  
Sandy Srinivas ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Locally Advanced ◽  
Sensory Neuropathy ◽  
Multiple Organ ◽  
Antibody Drug Conjugate ◽  
Metastatic Urothelial Carcinoma ◽  
Previously Treated ◽  
Muscle Invasive ◽  
Platinum Chemotherapy ◽  
Peripheral Sensory

441 Background: Platinum chemotherapy is the standard for patients (pts) with metastatic urothelial carcinoma (mUC) in the first line (1L) setting. In cisplatin-ineligible pts, gem/carbo is a standard therapy, but is poorly tolerated with limited durability and survival. PD-1/PD-L1 inhibitors, such as pembrolizumab (P), have shown promising durability in this setting for PD-L1 high patients. Enfortumab vedotin (EV) is an antibody-drug conjugate that delivers the microtubule-disrupting agent MMAE to cells expressing Nectin-4, which is highly expressed in UC. EV has shown activity in previously treated mUC. Initial EV + P data were previously presented (Hoimes ESMO 2019); this provides first durability data and an update on safety/ORR. Methods: This multicohort study (NCT03288545) evaluated the safety/activity of EV + P. We report a cohort of 1L cis-ineligible patients treated with EV 1.25 mg/kg + P. In each 3-week cycle, EV was administered on Days 1 and 8 and P on Day 1. The primary endpoint was safety/tolerability; secondary objectives included determination of recommended EV dose, ORR, DCR, DOR/PFS per RECIST v1.1, and OS. Results: As of 8 Oct 2019, 45 mUC pts (median age 69 yr [51–90]) received a median of 9 (range 1-22) cycles of EV + P. The most common treatment-emergent adverse events (AE) were fatigue (58%, 11% ≥G3), alopecia (53%), and peripheral sensory neuropathy (53%, 4% ≥G3). One pt died due to an AE reported as related (multiple organ failure). With a median follow-up of 11.5 mo, confirmed investigator-assessed ORR was 73.3% (95% CI, 58.1, 85.4) including 15.6% CRs; DCR was 93.3%. The ORR in pts with liver metastasis was 53.3% (8/15). The ORR in pts with available PD-L1 status was 78.6% in PD-L1 high (11/14) and 63.2% in PD-L1 low (12/19). Of the 33 responders, 18 (55%) have ongoing responses including 11 responses beyond 10 months. The median DOR was not reached (range 1.2 to 12.9+ mo). The median PFS was 12.3 mo (95% CI, 7.98, -). Conclusions: In 1L cis-ineligible pts with mUC, EV + P, a potential platinum free option, demonstrates promising activity and durability, with a manageable safety profile. Further evaluation of EV + P in mUC and muscle-invasive UC is ongoing. Clinical trial information: NCT03288545.

Docetaxel As Monotherapy or Combined With Ramucirumab or Icrucumab in Second-Line Treatment for Locally Advanced or Metastatic Urothelial Carcinoma: An Open-Label, Three-Arm, Randomized Controlled Phase II Trial

2016 ◽  
Vol 34 (13) ◽  
pp. 1500-1509 ◽  
Author(s):  
Daniel P. Petrylak ◽  
Scott T. Tagawa ◽  
Manish Kohli ◽  
Andrea Eisen ◽  
Christina Canil ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Urothelial Carcinoma ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
Vascular Endothelial ◽  
Line Treatment ◽  
Second Line ◽  
Metastatic Urothelial Carcinoma ◽  
Endothelial Growth Factor

Purpose This trial assessed the efficacy and safety of docetaxel monotherapy or docetaxel in combination with ramucirumab (vascular endothelial growth factor receptor 2 antibody) or icrucumab (vascular endothelial growth factor receptor 1 antibody) after progression during or within 12 months of platinum-based regimens for patients with locally advanced or metastatic urothelial carcinoma. Patients and Methods Patients were randomly assigned (1:1:1) to receive docetaxel 75 mg/m2 intravenously (IV) on day 1 of a 3-week cycle (arm A), docetaxel 75 mg/m2 IV plus ramucirumab 10 mg/kg IV on day 1 of a 3-week cycle (arm B), or docetaxel 75 mg/m2 IV on day 1 plus icrucumab 12 mg/kg IV on days 1 and 8 of a 3-week cycle (arm C). Treatment continued until disease progression or unacceptable toxicity. The primary end point was investigator-assessed progression-free survival (PFS). Results A total of 140 patients were randomly assigned and treated in arms A (n = 45), B (n = 46), or C (n = 49). PFS was significantly longer in arm B compared with arm A (median, 5.4 months; 95% CI, 3.1 to 6.9 months v 2.8 months; 95% CI, 1.9 to 3.6 months; stratified hazard ratio, 0.389; 95% CI, 0.235 to 0.643; P = .0002). Arm C did not experience improved PFS compared with arm A (1.6 months; 95% CI, 1.4 to 2.9; stratified hazard ratio, 0.863; 95% CI, 0.550 to 1.357; P = .5053). The most common grade 3 or worse adverse events (arms A, B, and C) were neutropenia (36%, 33%, and 39%), fatigue (13%, 30%, and 20%), febrile neutropenia (13%, 17%, and 6.1%), and anemia (6.7%, 13%, and 14%, respectively). Conclusion The addition of ramucirumab to docetaxel met the prespecified efficacy end point for prolonging PFS in patients with locally advanced or metastatic urothelial carcinoma receiving second-line treatment and warrants further investigation in the phase III setting.

Does escalation results from phase Ib/II Norse study of erdafitinib (ERDA) + PD-1 inhibitor JNJ-63723283 (Cetrelimab [CET]) in patients (pts) with metastatic or locally advanced urothelial carcinoma (mUC) and selected fibroblast growth factor receptor (FGFR) gene alterations.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 511-511 ◽  
Author(s):  
Victor Moreno ◽  
Yohann Loriot ◽  
Begona Pérez Valderrama ◽  
Carmen Beato ◽  
Yann-Alexandre Vano ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Locally Advanced ◽  
Growth Factor Receptor ◽  
Primary Endpoints ◽  
The Us ◽  
Metastatic Urothelial Carcinoma ◽  
Prior Systemic Therapy ◽  
Advanced Urothelial Carcinoma ◽  
Us Fda ◽  
Gene Alterations

511 Background: ERDA, an oral pan-FGFR inhibitor, is approved by the US FDA for pts with metastatic urothelial carcinoma (mUC) with susceptible FGFR3/2 gene alterations and progressed after ≥1 line of prior platinum-containing chemotherapy (PCC).1 CET, an IgG4, binds to anti-programmed cell death proteins (PD-1) and has shown activity in solid tumors.2 ERDA+CET may demonstrate complementary mechanisms as neoantigen release by ERDA may prime the tumor microenvironment for response. NORSE is a phase 1b/2 study to evaluate ERDA+CET in pts with mUC. Methods: Adult mUC pts with specific FGFR alterations who have progressed after ≥1 prior systemic therapy and no prior FGFR or PD-1/PD(L)-1 inhibitors enrolled in 3 dose levels (DL) of ERDA (DL1: 6 mg, DL2A: 8 mg, DL2: 8 mg with uptitration [UPT] to 9 mg) + CET (IV, 240 mg). Cohorts enrolled until dose limiting toxicity (DLT) or RP2D was identified. Primary endpoints: DLT and adverse events (AEs). Results: Of 15 pts (DL1: 4, DL2A: 3, DL2: 8), 11 continued on treatment at the time of the data cut. 14/15 pts experienced AEs; 3 experienced serious unrelated AEs (urinary tract infection, urosepsis, and large intestinal obstruction) all in DL1, 2 led to death; 10 experienced Grade >3 AEs and 2 experienced AEs of special interest, considered related to ERDA (Table). No DLTs were observed in any cohorts, 8 mg with UPT + CET was established as the RP2D. At data cut-off, investigator-assessed best overall response rate (CR+PR+uCR+uPR) in pts treated with the RP2D was 71% and disease control rate was 100% for RECIST 1.1 evaluable pts (n=7). Conclusions: 8 mg ERDA with UPT+240 mg CET was well tolerated and established as the RP2D. The combination of ERDA+CET is being further explored in the ongoing randomized phase 2 study in first-line cisplatin-ineligible mUC pts (NCT03473743). Clinical trial information: 2017-001980-19. [Table: see text]

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