San Francisco, CA USA (UroToday.com) The role for novel checkpoint blockade strategies in non-muscle invasive bladder cancer (NMIBC) is unclear. In the first of a “point-counterpoint” style debate, Dr. Svatek offered the urologists perspective and questioned the utility of immune checkpoint inhibition in NMIBC. From the urologist standpoint, the first step in papillary NMIBC is complete endoscopic removal. This differs slightly from the CIS setting in which its diffuse nature may preclude complete resection. Thus, the potential outcomes for adjuvant therapies are different; in the former case, recurrence rates can be evaluated while in the latter disease response to therapy is a more appropriate endpoint.
The options for checkpoint inhibition in NMIBC include those in delivery and population selection. With delivery, there are intravesical versus systemic options and monotherapy versus combination with BCG. In terms of treatment population, there are BCG naïve, BCG relapsing, and BCG unresponsive patients to consider. Within the last group, there has been some recent consensus in the definition including (1) failure to achieve complete response within 6 month of BCG initiation, (2) recurrence with T1HG after initial induction and/or (3) recurrence within 6 months of an initial complete response (Lerner S et al., Bladder Cancer 2015 and Jarow JP et al., Urology 2014). These definitions can help to clarify study populations and there is a recently approved phase 2 trial of MPDL3280A in BCG-unresponsive NMIBC (Black P and Singh P, SWOG).
The challenges for use of checkpoint inhibitors in NMIBC are the following: (1) the curative alternative, (2) lack of current evidence, and (3) real immune-related adverse events. Our worst fear with bladder sparing attempts in NMIBC is missing the window of opportunity for cure. Quoting Randy Millikan, Dr. Svatek noted that “there are some battles you can’t win, but you shouldn’t lose battles you can win.” He asked the question of whether immune-related responses would be adequate in NMIBC. In patients with metastatic urothelial carcinoma (mUC) in whom checkpoint inhibitors have been tested, there is often an increase in tumor burden prior to response (Wolchok et al., CCR 2009). Can we tolerate delayed responses in NMIBC? Powles and colleagues have demonstrated variability of response to checkpoint inhibition in the mUC setting (Nature 2014). Thus, it is unclear how many patients with NMIBC will benefit and what risk non-responders would be incurring by trying checkpoint inhibition prior to definitive local therapy.
There is currently a dearth of evidence that checkpoint inhibition will work in the NMIBC setting. Successful immunotherapy with BCG historically required small tumor burden, an adequate number of living BCG, and close contact between BCG and tumor (Zbar B et al., Cancer 1974). The mutational and molecular landscapes across bladder cancer stages from NMIBC to MIBC are quite different. Lund and colleagues have demonstrated that immune checkpoint alterations are also different between NMIBC and MIBC. Therefore, it is unclear that what has shown some benefit in the mUC setting will remain a viable alternative in the NMIBC setting.
Finally, the immune-mediated AEs are not trivial and include decreased appetite, fatigue, rash, diarrhea (30%), colitis (1-5%), hepatotoxicity (~5%), hypophysitis (<1%), and hypothyroidism (2-12%), and arthralgia (Mahzari et al., Clin Med Insights Endocrinol Diabetes 2015).
In conclusion, Dr. Svatek noted that NMIBC includes multiple distinct phenotypes which incur several challenges. The best chance may be in BCG-unresponsive phenotypes, but concerns for progression are real in this population. The results of several trials using checkpoint inhibition in NMIBC are eagerly anticipated. Combination therapy is the key to optimize future best care.
Presented By:
Robert S. Svatek, MD
The University of Texas Health Science Center at San Antonio
Reported By:
Benjamin T. Ristau, MD at the 2016 Genitourinary Cancers Symposium - January 7 - 9, 2016 – San Francisco, CA
Fox Chase Cancer Center, Philadelphia, PA