CUA 2017: Phase II Trial of Atezolizumab in Bacillus Calmette-Guérin-Unresponsive Non-Muscle-Invasive Bladder Cancer

Toronto, Ontario (UroToday.com) Immune checkpoint inhibitors (ICI) are a novel class of agents with promising results in multiple solid organ malignancies, typically in the advanced state. There are now 5 ICI’s approved for metastatic / advanced urothelial cancer (UC). However, while the promise of these therapies has been high, each has been shown to demonstrate an approximately 20% objective response rate (ORR), indicating the importance of patient selection. 

In the non-muscle invasive bladder cancer (NMIBC) arena, however, there has been very little progress beyond the use of BCG intravesical injections. In patients who are unresponsive to BCG, radical cystectomy (RC) still remains the standard of care. Unfortunately, many patients are medically unfit for surgery or would rather assume a risk of additional course of intravesical therapy before committing to cystectomy. 

With promise in the metastatic and advanced UC space, there are now ongoing trials evaluating ICI’s in BCG unresponsive NMIBC. The definition of BCG-unresponsive NMIBC is any of the following 3 criteria:

1. High grade Ta/Tis:
     - After at least induction and maintenance (5+2) or 2nd induction BCG
     - Within 6 months of last BCG dose

2. High grade T1 – after at least induction BCG

3. High grade Ta/Tis/T1 – recurrence within 6 months of last BCG dose in patients who reached a complete response

This is a multi-institutional SWOG single-arm non-randomized phase 2 trial. In this presentation Dr. Kassouf presented the design of this upcoming trial of atezolizumab in the setting of BCG unresponsive NMIBC. This trial tests systemic atezolizumab (1200 mg IV) every three weeks for one year in 135 patients with BCG-unresponsive, high-risk NMIBC. The final goal is to enroll 70 patients with carcinoma in situ (CIS) (with or without concomitant Ta/T1) and 65 with Ta/T1 only. The trial protocol includes patients with CIS at baseline needing to undergo mandatory repeat biopsy at six 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 six months in the CIS subgroup; and 2) event-free survival (EFS) at 18 months in the overall population. 

Secondary endpoints include duration of CR, as well as progression-free, cystectomy-free, bladder cancer-specific, and overall survival in all patients. As with most of the ICI trials, the response will be correlated to PD-L1 expression and CD8 expression by IHC, but also to molecular subtypes and immune signatures by RNA-sequencing.

According to the authors, promising results would include ≥28 (40%) CIS patients responding. 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).

Dr. Kassouf concluded by stating that he hopes to begin recruiting soon, and the results may help shape the treatment landscape of NMIBC. Similar trials using pembrolizumab are ongoing already.

Presented By: Wassim (Wes) Kassouf, MD, McGill University Health Centre, Montreal, Quebec 

Written By: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre  Twitter: @GoldbergHanan at the  72nd Canadian Urological Association Annual Meeting - June 24 - 27, 2017 - Toronto, Ontario, Canada
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