A randomized phase II study of erdafitinib (ERDA) versus intravesical chemotherapy (IC) in patients with high-risk nonmuscle invasive bladder cancer (HR-NMIBC) with FGFR mutations or fusions, who recurred after Bacillus Calmette-Guérin (BCG) therapy.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS603-TPS603 ◽  
Author(s):  
Gary D. Steinberg ◽  
Joan Palou-Redorta ◽  
Juergen E. Gschwend ◽  
Ben Tran ◽  
Yohann Loriot ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Treatment Options ◽  
Complete Response ◽  
Disease Recurrence ◽  
Subsequent Treatment ◽  
Invasive Bladder Cancer ◽  
Open Label ◽  
Bcg Therapy ◽  
Us Fda ◽  
To Receive

TPS603 Background: ERDA, an oral pan-FGFR inhibitor, is approved by the US FDA for metastatic urothelial carcinoma (mUC) with susceptible FGFR3 or FGFR2 gene alterations and progressed on/ or after at least 1 line of prior platinum-containing chemotherapy (PCC) including within 12 months of neoadjuvant/adjuvant PCC.1 Around 40% of patients with bladder cancer present with HR-NMIBC. First-line BCG therapy fails in 30-40% of patients and subsequent treatment options are limited. This study is designed to evaluate recurrence-free survival (RFS) following treatment with ERDA vs IC in patients with FGFR positive HR-NMIBC who recurred after BCG therapy. Methods: This is an open-label, multicenter, randomized, phase 2, safety and efficacy study of ERDA in adults with histologically confirmed HR-NMIBC and FGFR mutations or fusions. Inclusion criteria: ECOG status ≤1, adequate bone marrow, liver, renal function, and ineligibility for or declining cystectomy, with no history of prior FGFR inhibitors. Patients will be enrolled into 1 of 3 cohorts. Cohort 1 (n=240): high-grade disease Ta/T1 lesion (papillary only) with disease recurrence after BCG therapy will be randomized to ERDA or IC (investigator choice: gemcitabine or mitomycin C); Cohort 2 (n=20): carcinoma in situ (CIS) with/without papillary disease to receive ERDA monotherapy; Cohort 3 (n=20): marker lesion study in patients with intermediate-risk papillary disease only to receive ERDA monotherapy. Dose will be maintained at 8 mg, up-titrated to 9 mg, or withheld based on phosphate levels. Primary endpoint: Cohort 1- RFS; Secondary endpoints: Cohort 1 - time to progression and disease worsening, disease-specific survival (invasive bladder cancer), overall survival, RFS rate at 6, 12, 24 months, and RFS on subsequent anticancer therapy (RFS2). An IDMC will be commissioned for Cohort 1. Exploratory endpoints: Cohort 2- complete response (CR) rate at 6 months; Cohort 3- CR in marker lesion. Patients will be enrolled at sites in ~14 countries. EudraCT: 2019-002449-39. Loriot Y et al. N Engl J Med. 2019;381:338-48. Clinical trial information: 2019-002449-39.

scholarly journals Recognition and Treatment of BCG Failure in Bladder Cancer

2011 ◽  
Vol 11 ◽  
pp. 602-613 ◽  
Author(s):  
Andrew J. Lightfoot ◽  
Henry M. Rosevear ◽  
Michael A. O'Donnell
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Treatment Options ◽  
Standard Of Care ◽  
Complete Response ◽  
Bcg Therapy ◽  
Risk Patients ◽  
Bcg Failure ◽  
Muscle Invasive ◽  
American Urological Association

Patients with high-grade Ta, T1, or carcinomain situnon–muscle-invasive bladder cancer (NMIBC) are at high risk for recurrence and, more importantly, progression. Thus, both the American Urological Association and European Association of Urology recommend initial intravesical treatment with bacillus Calmette-Guerin(BCG) followed by maintenance therapy for a minimum of 1 year. The complete response rate to BCG therapy in patients with high-risk NMIBC can be as high as ∼80%; however, most patients with high-risk disease suffer from recurrence. BCG failure can be further characterized into BCG refractory, BCG resistant, BCG relapsing, and BCG intolerant. Current recommendations include one further course of BCG or cystectomy. In patients who continue to fail conservative treatment and who refuse surgical therapy or are not surgical candidates, treatment options become even more complicated. In this setting, treatment options are limited and include repeat BCG treatment, an alternate immunotherapy regimen, chemotherapy, or device-assisted therapy. To date, however, further research is necessary for all secondary treatment options in order to determine which might be the most efficacious. All conservative treatments should be considered investigational. Currently, cystectomy remains the standard of care for high-risk patients who have failed BCG therapy.

Phase II trial of atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer: SWOG S1605 (NCT #02844816).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5022-5022 ◽  
Author(s):  
Peter C. Black ◽  
Catherine Tangen ◽  
Parminder Singh ◽  
David James McConkey ◽  
Scott Lucia ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Phase Ii ◽  
Complete Response ◽  
Median Number ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Bladder Preservation ◽  
Bcg Therapy ◽  
Muscle Invasive

5022 Background: Radical cystectomy (RC) is the standard of care for patients with BCG-unresponsive high risk non-muscle invasive bladder cancer (NMIBC), but many patients are unfit for surgery or elect bladder preservation. Based on the reported efficacy of atezolizumab in metastatic urothelial carcinoma and the known expression of PD-L1 in NMIBC after BCG therapy, this trial was designed to evaluate the activity of atezolizumab in BCG-unresponsive high risk NMIBC. Methods: This single arm phase II registration trial testing systemic atezolizumab (1200 mg IV) every 3 weeks for one year aimed to enroll 135 (70 CIS and 65 non-CIS) eligible patients with histologically proven BCG-unresponsive high risk NMIBC who were unfit for or declined RC. Here we report on the subset with CIS (with or without concomitant Ta/T1) among patients who received at least one protocol treatment. The primary endpoint was pathological complete response (CR) rate at 6 months as defined by mandatory biopsy with a null hypothesis of 30% and alternative of 50% with a 1-sided alpha = 0.05 and 96% power. The 3 month CR rate, defined by cytology, cystoscopy and for-cause biopsy, is reported here as a secondary endpoint, in addition to safety. Results: Seventy-five eligible CIS patients were enrolled. Two received no treatment and are not evaluable. Of 73, median patient age was 73.4 years and median number of prior BCG doses was 12. Concomitant Ta/T1 tumor was found in 30 (41.1%) patients, including T1 disease in 16 (21.9%). A CR was observed in 30 (41.1%; 95% CI 29.7%, 53.2%) patients at 3 months and 19 (26.0%; 95% CI 16.5%, 37.6%) at 6 months. Any possibly or probably treatment-related adverse event (AE) was observed in 61 (83.6%) patients. The most frequent AEs were fatigue 36 (49.3%), pruritis 8 (11.0%), hypothyroidism 8 (11.0%), and nausea 8 (11.0%). Grade 3-5 AEs occurred in 9 (12.3%) patients and there was one treatment-related death (myasthenia gravis with respiratory failure and sepsis). Conclusion: The observed response to atezolizumab at 3 and 6 months in patients with BCG-unresponsive CIS was similar to that reported in recent similar trials and meets the benchmark for initial CR defined by the FDA guidance. This trial provided no new safety concerns. The duration of response will determine if this is a suitable treatment option for patients with BCG-unresponsive high risk CIS. Clinical trial information: 02844816 .

scholarly journals Avelumab as neoadjuvant therapy in patients with urothelial non-metastatic muscle invasive bladder cancer: a multicenter, randomized, non-comparative, phase II study (Oncodistinct 004 - AURA trial)

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Nieves Martinez Chanza ◽  
Louisa Soukane ◽  
Philippe Barthelemy ◽  
Aurélien Carnot ◽  
Thierry Gil ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Predictive Biomarkers ◽  
Complete Response ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Muscle Invasive ◽  
To Receive

Abstract Introduction Cisplatin-based neoadjuvant chemotherapy (NAC) followed by surgery is the standard treatment for patients with non-metastatic muscle invasive bladder cancer (MIBC). Unfortunately, many patients are not candidates to receive cisplatin due to renal impairment. Additionally, no predictive biomarkers for pathological complete response (pCR) are currently validated in clinical practice. Studies evaluating immune checkpoint inhibitors in the peri-operative setting are emerging with promising results. Clinical trials are clearly required in the neoadjuvant setting in order to improve therapeutic strategies. Methods and analysis Oncodistinct 004 – AURA is an ongoing multicenter phase II randomized trial assessing the efficacy and safety of avelumab single-agent or combined to different NAC regimens in patients with non-metastatic MIBC. Patients are enrolled in two distinct cohorts according to their eligibility to receive cisplatin-based NAC. In the cisplatin eligible cohort, patients are randomized in a 1:1 fashion to receive avelumab combined with cisplatin-gemcitabine or with dose-dense methotrexate-vinblastine-doxorubicin-cisplatin. In the cisplatin ineligible cohort, patients are randomized at a 1:1 ratio to paclitaxel-gemcitabine associated to avelumab or avelumab alone. Primary endpoint is pCR. Secondary endpoints are pathological response and safety. Ethics and dissemination The study is approved by ethics committee from all participating centers. All participants provide informed consent prior inclusion to the study. Once completed, results will be published in peer-reviewed journals. Trial registration number ClinicalTrials.gov (NCT03674424).

scholarly journals KEYNOTE-676: Phase III study of BCG and pembrolizumab for persistent/recurrent high-risk NMIBC

2020 ◽  
Vol 16 (10) ◽  
pp. 507-516 ◽  
Author(s):  
Ashish M Kamat ◽  
Neal Shore ◽  
Noah Hahn ◽  
Shaheen Alanee ◽  
Hiroyuki Nishiyama ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Treatment Options ◽  
Cancer Recurrence ◽  
Disease Recurrence ◽  
Current Treatment ◽  
Phase Iii ◽  
Bcg Therapy ◽  
Registration Number ◽  
Phase Iii Study

Background: Nonmuscle-invasive bladder cancer (NMIBC) is the most common form of bladder cancer, with high rates of disease recurrence and progression. Current treatment for high-risk NMIBC involves Bacillus Calmette-Guérin (BCG) therapy, but treatment options are limited for patients with recurrent or BCG-unresponsive disease. Aberrant programmed death 1 signaling has been implicated in BCG resistance and bladder cancer recurrence and progression, and pembrolizumab has shown efficacy in patients with BCG-unresponsive high-risk NMIBC. Aim: To describe the rationale and design for the randomized, comparator-controlled Phase III KEYNOTE-676 study, which will evaluate the efficacy and safety of pembrolizumab in combination with BCG in patients with persistent/recurrent high-risk NMIBC after BCG induction therapy. Trial registration number: NCT03711032

Pembrolizumab (pembro) for the treatment of patients with Bacillus Calmette-Guérin (BCG) unresponsive, high-risk (HR) non–muscle-invasive bladder cancer (NMIBC): Over two years follow-up of KEYNOTE-057.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5041-5041 ◽  
Author(s):  
Arjun Vasant Balar ◽  
Ashish M. Kamat ◽  
Girish S. Kulkarni ◽  
Edward M. Uchio ◽  
Joost L. Boormans ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Complete Response ◽  
Disease Recurrence ◽  
Intravesical Therapy ◽  
Efficacy Analysis ◽  
Bcg Therapy ◽  
Duration Of Response ◽  
Grade 3 ◽  
Muscle Invasive

5041 Background: Pembro was recently approved for the treatment of HR NMIBC based on results from the phase 2 KEYNOTE-057 (NCT02625961) study. Herein we present safety, efficacy, and posttreatment outcomes with > 2 y follow-up from KEYNOTE-057 cohort A. Methods: Patients with histologically confirmed HR BCG-unresponsive carcinoma in situ (CIS) with or without papillary tumors who received adequate BCG therapy and were ineligible for or opted out of radical cystectomy (RC) received pembro 200 mg Q3W for up to 2 y or until disease recurrence, progression, or unacceptable toxicity. The primary end point was complete response rate (CRR). Key secondary end points were duration of response (DOR) and safety. Results: Overall, 102 patients were initially enrolled, and 96 were included in the efficacy analysis. Median time from enrollment to data cut off was 28.4 months (range, 18.2-40.5). CRR was 40.6% (95% CI, 30.7-51.1), and median DOR was 16.2 months (range, 0+ to 30.4+). Among 39 patients with CR, 18 (46.2%) had a DOR ≥12 months. No patient’s disease progressed to muscle-invasive or metastatic bladder cancer while on study treatment. Median PFS and OS were not reached. At 12 months, PFS was 82.7% and OS was 97.9%. A total of 36 patients (37.5%) underwent RC after discontinuation from study treatment, which included 9 of 22 patients (40.9%) who had recurrence after initial CR and 27 of 57 (47.4%) nonresponders. Of the 36 who underwent RC, 33 (91.6%) had no pathological upstaging to MIBC and 3 (8.3%) had at least pT2 disease at time of RC. For subsequent treatments other than RC, 27 of 96 (28.1%) patients received additional intravesical therapy (eg, BCG, gemcitabine, or mitomycin), 21 of 96 (21.9%) underwent local procedures (eg, TURBT), and 3 of 96 (3.1%) received systemic therapy (eg, pembro). In 102 patients treated with pembro, treatment-related AEs (TRAEs) occurred in 67 (65.7%) patients; most frequently reported TRAEs were fatigue, pruritus, and diarrhea (10.8% each). Grade 3/4 TRAEs occurred in 13 patients (12.7%), and 21 patients (20.6%) experienced immune-mediated AEs. There were no grade 5 TRAEs. Conclusions: After > 2 y of follow-up, durable and clinically meaningful activity of pembro was observed in patients who had HR BCG-unresponsive CIS with or without papillary tumors and who were ineligible for or opted out of RC. Pembro did not seem to limit the opportunity for subsequent therapies, including RC. The safety profile was consistent with what is reported in the literature. Clinical trial information: NCT02625961 .

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