Erdafitinib in BCG-treated high risk non-muscle invasive bladder cancer

© 2023 The Author(s). Published by Elsevier Ltd on behalf of European Society for Medical Oncology. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Background: Treatment options are limited for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) with disease recurrence after bacillus Calmette–Guérin (BCG) treatment and who are ineligible for/refuse radical cystectomy. FGFR alterations are commonly detected in NMIBC. We evaluated the activity of oral erdafitinib, a selective pan-fibroblast growth factor receptor (FGFR) tyrosine kinase inhibitor, versus intravesical chemotherapy in patients with high-risk NMIBC and select FGFR3/2 alterations following recurrence after BCG treatment. Patients and methods: Patients aged ≥18 years with recurrent, BCG-treated, papillary-only high-risk NMIBC (high-grade Ta/T1) and select FGFR alterations refusing or ineligible for radical cystectomy were randomized to 6 mg daily oral erdafitinib or investigator's choice of intravesical chemotherapy (mitomycin C or gemcitabine). The primary endpoint was recurrence-free survival (RFS). The key secondary endpoint was safety. Results: Study enrollment was discontinued due to slow accrual. Seventy-three patients were randomized 2: 1 to erdafitinib (n = 49) and chemotherapy (n = 24). Median follow-up for RFS was 13.4 months for both groups. Median RFS was not reached for erdafitinib [95% confidence interval (CI) 16.9 months-not estimable] and was 11.6 months (95% CI 6.4-20.1 months) for chemotherapy, with an estimated hazard ratio of 0.28 (95% CI 0.1-0.6; nominal P value = 0.0008). In this population, safety results were generally consistent with known profiles for erdafitinib and chemotherapy. Conclusions: Erdafitinib prolonged RFS compared with intravesical chemotherapy in patients with papillary-only, high-risk NMIBC harboring FGFR alterations who had disease recurrence after BCG therapy and refused or were ineligible for radical cystectomy.Peer reviewe

Assessment of refinement techniques in aeroacoustic numerical simulations for helicopter rotors

Blade vortex interaction (BVI) noise is a major source of noise radiated by helicopter rotor in descent flight. The prediction of BVI noise requires that numerical simulation code can capture and follow small concentrated vortex structures in the midst of large extent of three dimensional time dependent wake structure. The highest possible resolution regarding loads and wake characteristics are expected to capture the tip vortex structure. In order to provide evidence and obtain guideline for high resolution simulations, the isolated main rotor calculation is carried out by partner DLR and NTUA in accordance with HeliNovi work description Task 1.1. The issue of scale refinement in BVI simulations for helicopter configurations is addressed in the NTUA GENUVP code [based on the vortex blob method and DLR UPM-Mantic code based on 3D free wake panel method. Since the highest possible scale refinement will result in severe penalty on computational cost, some numerical techniques are applied in both NTUA GENUVP code and DLR UPM code in order to speed-up the aerodynamic computation without sacrificing general accuracy. Results are presented for the BO105 rotor in descent flight, for four time steps down to 0.5 deg of azimuth angle increment and two panel grids. Aerodynamic and aeroacoustic properties are provided and discussed. The further improvement of BVI simulation by using tip vortex roll-up model is also addressed

Data on prior pegylated liposomal doxorubicin (PLD) treatment in recurrent ovarian cancer: Post-hoc data analysis from the phase 3 randomized, open-label study comparing trabectedin and PLD versus PLD alone in patients with recurrent ovarian cancer

The data presented herein are supplementary to our published primary article "A phase 3 randomized, open-label, multicenter trial for safety and efficacy of combined trabectedin and pegylated liposomal doxorubicin therapy for recurrent ovarian cancer"[1]. The exploratory analysis evaluated the impact of prior pegylated liposomal doxorubicin (PLD) therapy in patients who participated in a randomized, open-label study comparing combination therapy of trabectedin and PLD vs PLD alone in third-line recurrent ovarian cancer (ROC). These exploratory analyses showed that prior treatment with PLD in ROC does not impact the response and survival rates nor does it increase toxicities or negatively influence survival and response rates in both treatment groups. (C) 2020 The Author(s). Published by Elsevier Inc.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Cardiac safety of trabectedin monotherapy or in combination with pegylated liposomal doxorubicin in patients with sarcomas and ovarian cancer

BACKGROUND: As with other alkylating agents, cardiac dysfunction can occur with trabectedin therapy for advanced soft tissue sarcomas (STS) or recurrent ovarian cancer (ROC) where treatment options for advanced disease are still limited. Cardiac safety for trabectedin monotherapy (T) for STS or in combination with pegylated liposomal doxorubicin (T+PLD) for ROC was evaluated in this retrospective postmarketing regulatory commitment. METHODS: Patient data for multiple cardiac-related treatment-emergent adverse events (cTEAEs) were evaluated in pooled analyses of ten phase 2 trials, one phase 3 trial in STS (n = 982), and two phase 3 trials in ROC (n = 1231). RESULTS: Multivariate analyses on pooled trabectedin data revealed that cardiovascular medical history (risk ratio [RR (95% CI)]: 1.90 [1.24-2.91]; p = 0.003) and age ≥65 years (RR [95% CI]: 1.78 [1.12-2.83]; p = 0.014) were associated with increased risk for cTEAEs. Multivariate analyses showed increased risk of experiencing cTEAEs with T+PLD compared to PLD monotherapy (RR [95% CI]: 2.70 [1.75-4.17]; p \u3c 0.0001) and with history of prior cardiac medication (RR [95% CI]: 1.88 [1.16-3.05]; p = 0.010). CONCLUSIONS: For patients with STS or ROC who still have limited treatment options, trabectedin may be initiated after carefully considering benefit versus risk. Trial Registration (ClinicalTrials.gov): NCT01343277; NCT00113607; NCT01846611

Cardiac safety of trabectedin monotherapy or in combination with pegylated liposomal doxorubicin in patients with sarcomas and ovarian cancer

BackgroundAs with other alkylating agents, cardiac dysfunction can occur with trabectedin therapy for advanced soft tissue sarcomas (STS) or recurrent ovarian cancer (ROC) where treatment options for advanced disease are still limited. Cardiac safety for trabectedin monotherapy (T) for STS or in combination with pegylated liposomal doxorubicin (T+PLD) for ROC was evaluated in this retrospective postmarketing regulatory commitment.MethodsPatient data for multiple cardiac‐related treatment‐emergent adverse events (cTEAEs) were evaluated in pooled analyses of ten phase 2 trials, one phase 3 trial in STS (n = 982), and two phase 3 trials in ROC (n = 1231).ResultsMultivariate analyses on pooled trabectedin data revealed that cardiovascular medical history (risk ratio [RR (95% CI)]: 1.90 [1.24‐2.91]; p = 0.003) and age ≥65 years (RR [95% CI]: 1.78 [1.12‐2.83]; p = 0.014) were associated with increased risk for cTEAEs. Multivariate analyses showed increased risk of experiencing cTEAEs with T+PLD compared to PLD monotherapy (RR [95% CI]: 2.70 [1.75‐4.17]; p < 0.0001) and with history of prior cardiac medication (RR [95% CI]: 1.88 [1.16‐3.05]; p = 0.010).ConclusionsFor patients with STS or ROC who still have limited treatment options, trabectedin may be initiated after carefully considering benefit versus risk.Trial Registration (ClinicalTrials.gov): NCT01343277; NCT00113607; NCT01846611.Cardiac safety for trabectedin monotherapy advanced soft tissue sarcomas (STS) or in combination with pegylated liposomal doxorubicin (T+PLD) for recurrent ovarian cancer (ROC) was evaluated in pooled analyses of 10 phase 2 trials, one phase 3 trial in STS (n = 982), and two phase 3 trials in ROC (n = 1231). Cardiovascular medical history, age ≥65 years, and prior use of anthracyclines were associated with increased risk for cTEAEs. For patients with STS or ROC who still have limited treatment options, trabectedin may be initiated after carefully considering benefit versus risk.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/168318/1/cam43903_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/168318/2/cam43903.pd

Phase 2 Study of the Efficacy and Safety of Erdafitinib in Patients With Bacillus Calmette-Guérin (BCG)-Unresponsive, High-Risk Non–Muscle-Invasive Bladder Cancer (HR-NMIBC) With FGFR3/2 Alterations (alt) in THOR-2: Cohort 2 Interim Analysis Results

© 2023 American Society of Clinical Oncology (ASCO). All Rights Reserved Worldwide.Patients presenting with NMIBC carcinoma in situ (CIS) have a high risk of progression1,2FGFR inhibition may benefit patients with CIS with FGFRalt who are unresponsive to fi rst-line BCG, for whom treatment options, other than radical cystectomy, are limited3-5– Data are limited in patients with CIS only, but in the broader NMIBC population the prevalence of FGFR3alt is up to 80%6Erdafi tinib, an oral selective pan-FGFR tyrosine kinase inhibitor, is approved for locally advanced or metastatic urothelial cancer in adults with susceptible FGFR3/2alt who have progressed during or after ≥1 line of platinum-containing chemotherapy7-9 THOR-2 (NCT04172675) is a multicohort phase 2 study of erdafi tinib in patients with HR-NMIBC.Peer reviewe

Management of Fibroblast Growth Factor Inhibitor Treatment–emergent Adverse Events of Interest in Patients with Locally Advanced or Metastatic Urothelial Carcinoma

Background: Erdafitinib is indicated for the treatment of adults with locally advanced/metastatic urothelial carcinoma and susceptible FGFR3/2 alterations progressing on/after one or more lines of prior platinum-based chemotherapy. Objective: To better understand the frequency and management of select treatment-emergent adverse events (TEAEs) to enable optimal fibroblast growth factor receptor inhibitor (FGFRi) treatment. Design, setting, and participants: Longer-term efficacy and safety results of the BLC2001 (NCT02365597) trial in patients with locally advanced and unresectable or metastatic urothelial carcinoma were studied. Intervention: Erdafitinib schedule of 8 mg/d continuous in 28-d cycles, with uptitration to 9 mg/d if serum phosphate level was <5.5 mg/dl and no significant TEAEs occurred. Outcome measurements and statistical analysis: Adverse events were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The Kaplan-Meier methodology was used for the cumulative incidence of the first onset of TEAEs by grade. Time to resolution of TEAEs was summarized descriptively. Results and limitations: At data cutoff, the median treatment duration was 5.4 mo among 101 patients receiving erdafitinib. Select TEAEs (total; grade 3) were hyperphosphatemia (78%; 2.0%), stomatitis (59%; 14%), nail events (59%; 15%), non–central serous retinopathy (non-CSR) eye disorders (56%; 5.0%), skin events (55%; 7.9%), diarrhea (55%; 4.0%), and CSR (27%; 4.0%). Select TEAEs were mostly of grade 1 or 2, and were managed effectively with dose modifications, including dose reductions or interruptions, and/or supportive concomitant therapies, resulting in few events leading to treatment discontinuation. Further work is needed to determine whether management is generalizable to the nonprotocol/general population. Conclusions: Identification of select TEAEs and appropriate management with dose modification and/or concomitant therapies resulted in improvement or resolution of most TEAEs in patients, allowing for continuation of FGFRi treatment to ensure maximum benefit. Patient summary: Early identification and proactive management are warranted to mitigate or possibly prevent erdafitinib side effects to allow for maximum drug benefit in patients with locally advanced or metastatic bladder cancer