Checkpoint Inhibitors Hold Promise for BCG-Unresponsive NMIBC

Stephen A. Boorjian, MD

The established efficacy of single-agent checkpoint inhibition for metastatic urothelial carcinoma along with molecule expression analyses suggests that PD-1/PD-L1 inhibition could hold promise for patients with non-muscle invasive bladder cancer (NMIBC), particularly those unresponsive to Bacillus Calmette-Guérin (BCG), according to a presentation by Stephen A. Boorjian, MD, at the 2017 SUO Annual Meeting.

The definition of BCG unresponsiveness is nuanced, based on the grade and extent of the disease. For those who do not respond within 1 year or following 2 induction cycles of BCG, the next treatment is typically radical cystectomy. For patients who are unwilling or unable to undergo cystectomy, guidelines suggest that clinicians recommend clinical trial enrollment.

“I think radical cystectomy has to remain the gold standard of therapy in 2017 for BCG-unresponsive NMIBC,” noted Boorjian, a urologist at the Mayo Clinic. “The concept of this definition [of unresponsiveness] is to identify patients who are not going to benefit from additional BCG therapy."

Given the complications associated with cystectomy, there is a need for more effective therapies for NMIBC, specifically given recent BCG shortages. Checkpoint inhibition offers a viable alternative, given its activity in metastatic urothelial carcinoma. Multiple agents are now approved by the FDA both in the second-line metastatic setting and as first-line therapy for platinum-ineligible metastatic disease.

Adding to this, NMIBC is an immune sensitive disease. “We have decades of evidence showing us that NMIBC is an immune-sensitive disease, as shown by its response to BCG intravesical therapy,” Boorjian said. BCG is thought to work via immune-related pathways, as there is an increase in cytokine secretion and upregulation of TH1 immune response during its administration.

Adding to the establish immunosensitivity, Boorjian noted that a study investigating PD-L1 expression across bladder cancer tumor stages demonstrated the highest expression of PD-L1 in patients who had carcinoma in situ, and a 15- to 20-fold increase of expression was seen in patients with carcinoma in situ recurrence after BCG therapy.

“We did a subsequent study looking at PD-1 expression on tumor infiltrating lymphocytes and likewise found significant increase in expression in patients treated with BCG, and a correlation of expression on tumor infiltrating lymphocytes of PD-1 with tumor expression of PD-L1,” Boorjian said.

There are currently trials of checkpoint inhibitors that are open for patients with NMIBC, which could represent an important alternative to cystectomy. There is the phase II SWOG S1605 trial of atezolizumab (Tecentriq) in BCG unresponsive NMIBC (NCT02844816), and the phase II KEYNOTE-057 trial of pembrolizumab (Keytruda) in patients with high-risk NMIBC (NCT02625961). There is also a phase I/II trial, ADAPT-BLADDER, investigating durvalumab (Imfinzi) in BCG-relapsed urothelial carcinoma (NCT03317158).

However, Boorjian cautioned that there are uncertainties and concerns regarding checkpoint inhibitors for NMIBC. The activity of checkpoint inhibitors in NMIBC itself remains unknown at this point, and so participation in clinical trials is paramount. The importance of expression of checkpoint blockade biomarkers in NMIBC is also unestablished, and there is conflicting evidence concerning the importance of expression in the metastatic setting.

Clinicians also need to be mindful of adverse effects the drugs may have on their patients, he said. “We have to balance the potential toxicities of treatment versus the potential lethality of the disease; these are often elderly or comorbid populations of patients not fit for cystectomy, so how they are going to handle potential immune-related adverse effects of these medications remains to be determined,” Boorjian said.

Boorjian SA. Promise of checkpoint inhibitors for BCG-unresponsive NMIBC: how excited should we be? Presented at: 2017 SUO Annual Meeting; November 29-December 1, 2017; Washington, DC.