SUO 2017: Promise of Checkpoint Inhibitors for BCG-Unresponsive NMIBC

Washington, DC ( BCG remains the best intravesical treatment for patients with high grade (HG) non-muscle invasive bladder cancer (NMIBC). Unfortunately, 30% of patients with HG NMIBC will not respond to BCG leaving the treating physician with very little options in the care of these patients. In accordance with the most recent AUA/SUO and NCCN guidelines patients deem BCG-refractory should be offered an early cystectomy. However, there are a subset of this patients in whom a radical cystectomy may not be indicated or who would like to preserve their bladder. For these subgroup of patients, the available intravesical options are limited and provide a modest response rate. The growing success of checkpoint inhibitors in patients with advance bladder cancer has led the study of these agents in the BCG-refractory setting. 

Dr. Stephen Boorjian, from the Mayo Clinic in Rochester, presents the available evidence for the use of checkpoint inhibitors in patients with BCG-refractory NMIBC. The failure of several chemotherapy agents in the BCG-refractory space has led some to conclude that immunotherapy, like BCG, may be the best treatment for these patients. This notion is supported by recent work showing an increase expression of the PD-L1 ligand in tumors following treatment with BCG. Further work has shown a complementary increased expression of the PD-1 receptor in tumor infiltrating lymphocytes, a sign of lymphocyte exhaustion, which could be associated with tumor resistance to BCG. Together this evidence supports the use of checkpoint inhibitor in patients with BCG refractory disease. Currently there are three trials (SWOG S1605, Keynote-057, and ADAPT) assessing the role of PD-1 inhibitors in the BCG-refractory setting. SWOG S1605 and Keynote-057 have similar designs in which a PD-1 inhibitor (atezolizumab or pembrolizumab) is infused every 3 weeks for 3 months followed by cystoscopic surveillance and staging imaging every 6 months for 2 years.  The ADAPT trial differs in that the added value of BCG and radiation therapy to checkpoint inhibition (durvalumab) will be assessed in separate arms, allowing for some novel comparisons.

While there is significant excitement of the potential used of these agents in patients BCG-refractory disease, one must be reminded that the activity of checkpoint inhibitors in this setting remains completely theoretical. As it has been noted in those with metastatic disease PD-L1 expression in bladder cancer tumors have not been associated with improved response rates, thus we cannot assert that the high PD-L1 expression of BCG refractory tumors will a surrogate for treatment response. Lastly, the side effects of checkpoint inhibitors (pneumonitis, hepatitis and colitis) can be severe and life threatening, and these should be weighted carefully in those elderly and frail patients who commonly present with the disease. 

In summary, there is a theoretical rationale for the use of check-point inhibitors in patients presenting with BCG-refractory disease; however, data to support this rationale remains lacking. The recommendation for patients with BCG-refractory disease remains an early cystectomy and any intravesical treatment of these patients should be done in a clinical trial.    

Presented by: Stephen A. Boorjian MD, Professor of Urology at the Mayo Clinic in Rochester, MN 

Written by: Andres F. Correa, Society of Urologic Oncology Fellow, Fox Chase Cancer Center-Temple Health, Philadelphia, PA  at the 18th Annual Meeting of the Society of Urologic Oncology, November 20-December 1, 2017 – Washington, DC