Pembro shows promising antitumor activity

Pembrolizumab (Keytruda) is showing encouraging antitumor activity in an ongoing phase II study including patients with high-risk, nonmuscle-invasive bladder cancer that is unresponsive to bacillus Calmette-Guérin treatment.

Pembrolizumab (Keytruda) is showing encouraging antitumor activity in an ongoing phase II study including patients with high-risk, nonmuscle-invasive bladder cancer that is unresponsive to bacillus Calmette-Guérin (BCG) treatment.

Treatment with the PD-1 monoclonal antibody as monotherapy produced a 41.2% complete response rate in an updated analysis including 102 patients with BCG-unresponsive carcinoma in situ who were ineligible for radical cystectomy or refused it, according to investigator Ronald de Wit, MD, PhD, professor of internal oncology at Erasmus University Medical Center, Rotterdam, the Netherlands.

The median duration of complete response was 13.5 months as of this update, though further follow-up is needed, Dr. de Wit told Urology Times. He presented the data at the American Society of Clinical Oncology annual meeting in Chicago.

“It’s a strong signal at this point,” he said in an interview. “What would matter for a patient is the likelihood that the cystectomy can ultimately be avoided, so I think it would be meaningful if it would be 3-plus years.”

Activation of the PD-1 pathway has been linked to BCG resistance, according to Dr. de Wit and his co-authors. Pembrolizumab, which blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2, is active in metastatic urothelial carcinoma and has become a standard of care in that setting for certain patients.

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The phase II study, known as KEYNOTE-057, enrolled patients with high-risk nonmuscle-invasive bladder cancer. The study included two cohorts, including one group of patients with carcinoma in situ with or without papillary disease, which was discussed by Dr. de Wit, and a second group of patients with papillary disease but no carcinoma in situ.

In the carcinoma in situ cohort, a total of 102 patients were treated with pembrolizumab, 200 mg every 3 weeks for up to 2 years. The median age of these patients was 73 years, about 83% were male, and the median number of prior BCG instillations was 12.

Complete responses were seen in 42 patients, or 41.2% (95% CI, 31.5-51.4), Dr. de Wit reported. As of this update, 52.4% had ongoing responses, and the median duration of complete response was 13.5 months (range, 0+ to 26.8+ months).

The adverse event profile of pembrolizumab for these patients with nonmuscle-invasive bladder cancer in KEYNOTE-057 was consistent with what has been observed in studies of pembrolizumab as first- and second-line treatment of advanced urothelial carcinoma, according to Dr. de Wit.

Treatment-related adverse events occurred in about two-thirds of patients, and 13 (12.7%) were grade 3 or 4, according to the report. Discontinuations due to treatment-related adverse events were reported in nine patients, or 8.8%. Immune-related adverse events, characteristic of pembrolizumab and other checkpoint inhibitors, occurred in about 20% of patients, and of those, three (2.9%) reached grade 3 or 4.

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With further follow-up pending, these findings to date suggest pembrolizumab monotherapy could represent an option to avoid radical cystectomy, Dr. de Wit said.

“None of these patients who ultimately failed had progressed to muscle-invasive disease, so we didn’t waste an opportunity. Some failed, but then they underwent the cystectomy,” he added.

Ninety-five percent of the enrolled patients had no prior cystectomy because they had refused it, and only about 3% because they were ineligible for the procedure, according to reported data.

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“If you are talking with patients about what to do, most of them want to keep the bladder in, and are keen to be on a study like this,” Dr. de Wit said.

Currently enrolling is KEYNOTE-676, a phase III study looking at the efficacy and safety of pembrolizumab plus BCG in high-risk nonmuscle-invasive bladder cancer that is persistent or recurrent after induction with BCG.

Dr. de Wit has received honoraria from Merck and Sanofi; is a consultant/adviser to Bayer, Clovis, Janssen, Merck, Roche/Genentech, and Sanofi; has received institutional funding from Bayer and Sanofi; and has received travel, accommodations, and expenses from Lilly. Several of his co-authors have disclosures related to one or more pharmaceutical companies; for full disclosures, see