Results from BLASST-1 (Bladder Cancer Signal Seeking Trial) of nivolumab, gemcitabine, and cisplatin in muscle invasive bladder cancer (MIBC) undergoing cystectomy.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 439-439 ◽  
Author(s):  
Shilpa Gupta ◽  
Guru Sonpavde ◽  
Christopher J. Weight ◽  
Bradley Alexander McGregor ◽  
Sumati Gupta ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Phase Ii Trial ◽  
Molecular Subtypes ◽  
Alternative Hypothesis ◽  
Muscle Invasive Bladder Cancer ◽  
Sample Proportion ◽  
Pre Treatment ◽  
Grade 3 ◽  
Muscle Invasive ◽  
Clinical Trial Information

439 Background: Cisplatin-based neoadjuvant chemotherapy (NAC) in MIBC improves survival which correlates with pathologic response (PaR) at radical cystectomy (RC). The combination of immunotherapy and NAC may improve PaR and outcomes in MIBC. We tested the efficacy and safety of nivolumab (N) with gemcitabine-cisplatin (GC) as neoadjuvant therapy for MIBC in our phase II trial (NCT03294304). Methods: Eligible pts with MIBC (cT2-T4a, N≤1, M0) who were candidates for RC were enrolled. Pts received C (70mg/m2) IV on D1, G (1000mg/m2) on D1,D8 and N (360 mg) IV on D8 every 21 days for 4 cycles followed by RC within 8 weeks. The primary endpoint was PaR (≤pT1,N0). Secondary objectives were safety of GC+N and PFS at 2 years. The correlative objectives based on pre-treatment biopsies were correlation of PaR with 1) WGS 2) molecular subtypes of BC; 3) PD-L1 expression; 4) baseline TILs, CD3, CD8 and CD56.. Evaluable pts. should have received at least 1 dose of N. PaR will be summarized by the PaR rate as estimated by the sample proportion with exact 95% confidence intervals. We specified a null PaR of 0.35 and an alternative hypothesis of 0.55; we will reject the null hypothesis if at least 20 of 41 pts. have a PaR. Results: Between Feb 2018 and June 2019, 41 pts. were enrolled (cT2N0 90%, cT3N0 7%, cT4N1 3%); 2 patients refused surgery but were included in ITT population. PaR was observed in 27/41 pts. (65.8%), including pts with N1 disease. The combination was safe with manageable toxicities and no deaths from treatment. Majority of AEs were from GC; the overall rates of grade 3-4 AEs was 20%, majority being neutropenia, thrombocytopenia and renal insufficiency. Immune related AEs were seen in 3 patients, 2 had "adenitis" which wasymptomatic,1 pt developed Guillian Barre Syndrome after surgery, which resolved with IVIG; and none of them required steroids. There was no delay in time to RC and no unexpected surgical complications from treatment. Patients are being followed for progression and survival. Correlative work is ongoing. Conclusions: Neoadjuvant N+GC is safe and effective in MIBC with significant pathologic downstaging rates and no added toxicities or delay to surgery. Clinical trial information: NCT03294304.

scholarly journals Intratumoral heterogeneity of surrogate molecular subtypes in urothelial carcinoma in situ of the urinary bladder: implications for prognostic stratification of high-risk non-muscle-invasive bladder cancer

2021 ◽  
Author(s):  
Stefan Garczyk ◽  
Felix Bischoff ◽  
Ursula Schneider ◽  
Reinhard Golz ◽  
Friedrich-Carl von Rundstedt ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Carcinoma In Situ ◽  
Molecular Subtypes ◽  
Smoking Status ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Prognostic Stratification ◽  
Muscle Invasive

AbstractReliable factors predicting the disease course of non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) are unavailable. Molecular subtypes have potential for prognostic stratification of muscle-invasive bladder cancer, while their value for CIS patients is unknown. Here, the prognostic impact of both clinico-pathological parameters, including CIS focality, and immunohistochemistry-based surrogate subtypes was analyzed in a cohort of high-risk NMIBC patients with CIS. In 128 high-risk NMIBC patients with CIS, luminal (KRT20, GATA3, ERBB2) and basal (KRT5/6, KRT14) surrogate markers as well as p53 were analyzed in 213–231 biopsies. To study inter-lesional heterogeneity of CIS, marker expression in independent CIS biopsies from different bladder localizations was analyzed. Clinico-pathological parameters and surrogate subtypes were correlated with recurrence-free (RFS), progression-free (PFS), cancer-specific (CSS), and overall survival (OS). Forty-six and 30% of CIS patients exhibited a luminal-like (KRT20-positive, KRT5/6-negative) and a null phenotype (KRT20-negative, KRT5/6-negative), respectively. A basal-like subtype (KRT20-negative, KRT5/6-positive) was not observed. A significant degree of inter-lesional CIS heterogeneity was noted, reflected by 23% of patients showing a mixed subtype. Neither CIS surrogate subtype nor CIS focality was associated with patient outcome. Patient age and smoking status were the only potentially independent prognostic factors predicting RFS, PFS, OS, and PFS, respectively. In conclusion, further clarification of heterogeneity of surrogate subtypes in HR NMIBC and their prognostic value is of importance with regard to potential implementation of molecular subtyping into clinical routine. The potential prognostic usefulness of patient age and smoking status for high-risk NMIBC patients with CIS needs further validation.

Neoadjuvant accelerated MVAC therapy in bladder cancer: toxicity and efficacy correlation

2015 ◽  
Vol 3 (4) ◽  
pp. 582-594
Author(s):  
William M. Grabstald ◽  
Richard H. Sarkis ◽  
Chrisophos A. Jacobus ◽  
Smith V. Feifer
Keyword(s):  
Bladder Cancer ◽  
Radical Cystectomy ◽  
Cancer Staging ◽  
Invasive Disease ◽  
Fourth Edition ◽  
Muscle Invasive Bladder Cancer ◽  
Common Cancer ◽  
Node Metastases ◽  
Grade 3 ◽  
Muscle Invasive

Bladder cancer is the second most common cancer of the genitourinary tract. Radical cystectomy is considered the gold standard of treatment for patients with localized muscle-invasive disease (MIBC), although chemoradiotherapy protocols using neoadjuvant cisplatin-based chemotherapy is used for muscle-invasive bladder cancer. We explored the toxicity and efficacy of neoadjuvant AMVAC in MIBC. A total of 177 patients with clinical tumor–node–metastases (TNM) stage T2N0M0 to T4aN0M0 bladder cancer who were candidates for radical cystectomy were eligible, tumors were staged according to the criteria in the fourth edition of the American Joint Committee on Cancer staging manual. Grade ≥ 2 toxicities were observed in 8% of patients, with grade 3 and 4 neutropenia in 7% and 5% patients, respectively; grade 3 and 4 anemia in 4% and 2% of patients, respectively; no patients died of drug toxicity; 61% of patients were accrued; 16% were down-staged to non–muscle invasive disease. Further, 31% showing pT0 at cystectomy and the median survival was 16.9 months.

S1605: Phase II trial of atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS4591-TPS4591 ◽  
Author(s):  
Parminder Singh ◽  
Tangen Catherine ◽  
Seth P. Lerner ◽  
David McConkey ◽  
Melissa Plets ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Invasive Bladder Cancer ◽  
Type I ◽  
Muscle Invasive Bladder Cancer ◽  
Primary Endpoints ◽  
Bcg Therapy ◽  
Muscle Invasive

TPS4591 Background: Radical cystectomy is the standard of care for patients with BCG-unresponsive high risk non-muscle invasive bladder cancer (NMIBC). Based on the reported efficacy of atezolizumab in metastatic urothelial carcinoma and the known expression of PD-L1 expression in NMIBC after BCG therapy, this trial will evaluate the activity of atezolizumab in BCG-unresponsive high risk NMIBC. Methods: This is a single arm phase II trial testing systemic atezolizumab (1200 mg IV) every 3 weeks for one year in 135 patients with BCG-unresponsive high risk NMIBC. The study will enroll 70 patients with CIS (with or without concomitant Ta/T1) and 65 with Ta/T1 only. Patients with CIS at baseline will undergo mandatory repeat biopsy at 6 months, and all other patients only for suspected recurrence. Patients with persistent CIS, high grade Ta/T1 recurrence or progression to muscle invasive or metastatic disease will be taken off treatment. The co-primary endpoints are: (1) complete response (CR) at 6 months in the CIS subgroup, and (2) event-free survival (EFS) at 18 months in the overall population. A hierarchical approach will be used to test the two co-primary endpoints. Secondary endpoints include duration of CR as well as progression-free, cystectomy-free, bladder cancer-specific and overall survival in all patients. Response will be correlated to expression of PD-L1 and CD8 by IHC, and to molecular subtypes and immune signatures by RNA-sequencing. Results: If ≥28 (40%) CIS patients respond, the agent will be considered promising. This design has a significance level of 4.6%, and a power of 96%. If the lower bound of the 90% confidence interval of the 18-month EFS excludes 20%, the investigators will conclude the regimen significantly improves EFS relative to historical data (type I error rate 0.05 and statistical power 0.93). Conclusion:Successful completion of this trial could lead to a new treatment paradigm for patients with BCG-unresponsive high risk NMIBC. Funding: NIH/NCI grants: CA180888, CA180819, CA180820, CA180821, and CA180863. Clinical trial information: NCT02844816.

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