Andrew Bowser

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-GuÃ©rin (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 

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.

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 

Articles

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.

Pembro shows promising antitumor activity

Pyruvate kinase, a primary driver of tumor glycolysis, is promising both as a biomarker of bladder cancer and as a drug target, researchers reported at the 2018 Society of Urologic Oncology annual meeting in Phoenix.

Growing bladder cancer cells in increasing concentrations of glucose resulted in upregulation in the expression of tumor M2-PK, the dimeric form of the pyruvate kinase M2 isoenzyme, according to the researchers.

Moreover, exposing bladder cancer cell lines to a pyruvate kinase inhibitor reduced cell proliferation and caused switching of pyruvate kinase isoforms, said researcher Eugene K. Lee, MD, assistant professor of urology in the division of urologic oncology at the University of Kansas Medical Center, Kansas City.

Routine PET/CT not beneficial for node-negative patients

Although these are early findings, they do suggest potential implications for evaluation and treatment of bladder cancer at some point in the future, Dr. Lee said in an interview with 

“Clearly, metabolism is important for bladder cancer, so I do think that we could potentially use this as a urinary marker-either as an adjunct to cystoscopy, or potentially as an alternative to cystoscopy, which would be an ideal goal, though I think that we’re far from that,” he said.

Bladder cancer cells have a high affinity for glucose and depend on a shift to aerobic glycolysis-dependent metabolism, which is known as the Warburg effect, and pyruvate kinase is a principal driver of that effect, investigators said.

Pyruvate kinase M2 oscillates between an inactive dimer, which predominates in bladder cancer, and active tetrameter, they noted.

In their research, presented as a poster at the SUO annual meeting, Dr. Lee and co-investigators exposed two bladder cancer cell lines after exposure to varying concentrations of glucose, and then assessed cell proliferation and protein expression of pyruvate kinase M2.

Significant increases in cell proliferation and upregulation of pyruvate kinase M2 expression were seen when they exposed cells to higher glucose levels, they reported.

Compared to the standard 100-mg/dL glucose level, a 200-mg/dL level resulted in a twofold increase in growth rate for UM-UC-3 cells (urinary bladder transitional cell carcinoma) cells, and a 1.7-fold increase in HTB-9 cells (urinary bladder, grade II carcinoma).

Conversely, when glucose was reduced to 25 mg/dL, there was a 3.75-fold decrease in growth rate in UM-UC-3 cells and a 2.8-fold decrease in HTB-9 cells, the data show.

Dr. Lee and colleagues also evaluated the effects of shikonin, a pyruvate kinase inhibitor, in inhibiting cancer cell proliferation at various glucose concentrations.

Shikonin treatment not only inhibited cell proliferation, they found, but resulted in switching of the pyruvate kinase M2 isoforms from the bladder cancer-associated dimeric form (M2-PK) to the tetrameter form.

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In patient samples, dimeric tumor M2-PK has been significantly correlated with presence of bladder cancer, the investigators noted.

The poster was presented by co-investigator Meredith Metcalf, MD, of the University of Kansas.

Pyruvate kinase appears to be bladder cancer marker

Routine use of positron emission tomography/computed tomography prior to radical cystectomy is unlikely to benefit clinically node-negative patients, results of a recent investigation suggest.

Instead, the primary role of PET/CT appears to be further evaluation of enlarged nodes identified by CT, according to the study authors, who looked at the diagnostic properties of PET/CT in more than 200 patients with muscle-invasive urothelial carcinoma.

Based on the findings, PET/CT should be used when its results would impact patient management, such as the patient with clinically positive lymph nodes that would benefit from further characterization, according to first author Shawn Dason, MD, a urologic oncology fellow at Memorial Sloan Kettering Cancer Center, New York.

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“We are seeing PET/CT being increasingly performed as a routine preoperative test before radical cystectomy, but this is unlikely to benefit most patients without a suspicious CT scan,” Dr. Dason said in an interview with 

The study, presented at the 2018 Society of Urologic Oncology annual meeting in Phoenix by co-author Nathan C. Wong, MD, also a urologic oncology fellow at Memorial Sloan Kettering, included 208 patients with muscle-invasive urothelial carcinoma who underwent routine preoperative PET/CT and pelvic lymph node dissection at that institution between 2012 and 2017. That cohort included 170 patients with clinically node-negative disease and 38 with clinically node-positive disease.

Based on the present study’s findings, PET/CT is no longer routinely performed at the institution in patients with a regular CT scan demonstrating no suspicion of lymph node or distant metastases, according to Dr. Dason, who worked on the study with Bernard H. Bochner, MD, and colleagues.

Specifically, PET/CT rarely detected pathologically node-positive disease, with a sensitivity of 7% to 23% on a per-patient or per-region level and regardless of chemotherapy status, according to the findings.

By contrast, a negative PET/CT was useful in ruling out positive lymph node disease, according to investigators, with a sensitivity of 92% to 100% and a specificity of 63% to 81%.

That suggests PET/CT can help eliminate uncertainty as to whether patients with small but enlarged nodes truly have actual lymph node metastases, according to the investigators.

Minimally invasive cystectomy linked with shorter hospital stay

“These patients could have a biopsy, but this is invasive, and some of these lesions are difficult to biopsy,” said Dr. Dason.

These findings corroborate results of an earlier study in a more advanced setting. That 

, published in 2010 by investigators at Memorial Sloan Kettering and Weill Medical College of Cornell University, suggested that a negative PET/CT result was helpful in ruling out metastatic involvement of a suspicious lesion on CT scan 

The benefit of routine preoperative PET/CT in earlier disease was unclear based on the results of earlier investigations, according to Dr. Dason. Those studies included heterogeneous patient populations and varied in terms of how they handled preoperative chemotherapy and clinically suspicious lymph nodes on a regular CT scan.

Compared to an open approach, minimally invasive radical cystectomy was associated with a near 2-day shorter hospital stay in bladder cancer patients treated at diverse institutions across the United States, according to authors of a recent retrospective analysis of Medicare claims.

There was no difference in readmission rates for minimally invasive versus open radical cystectomy, while the cost to Medicare was nearly $4,000 less for the minimally invasive procedure, according to the analysis, which was presented at the 2018 Society of Urologic Oncology annual meeting in Phoenix and published in 

“The real-world practice of robotic cystectomy appears to line up with that in high-volume centers in randomized trials, which is reassuring for us,” said researcher Parth K. Modi, MD, MS, a urologic oncology and health services research fellow at the University of Michigan, Ann Arbor, working with Chad Ellimoottil, MD, MS, and colleagues.

Specifically, these findings confirm and extend those of the randomized RAZOR trial, Dr. Modi told 

 In that phase III, non-inferiority study, which included 350 patients treated at 15 high-volume, specialized centers, median length of stay was significantly shorter for those patients who underwent robot-assisted radical cystectomy versus those who underwent an open procedure 

However, cost data in RAZOR were unsuitable for analysis, according to investigators, who cited “considerable heterogeneity” in data among centers and an inability to collect data from all participating centers due to proprietary concerns.

For the analysis presented at the SUO annual meeting, Dr. Modi and colleagues looked at 4,760 Medicare patients with bladder cancer who underwent radical cystectomy between 2008 and 2015. Of those patients, 693 (14.6%) underwent a minimally invasive procedure, while the remaining 4,067 (85.4%) were open.

Length of stay was a median 10.1 days for the minimally invasive procedure versus 11.9 days for the open procedure 

<.001) after adjusting for patient, hospital, and surgeon factors, Dr. Modi and colleagues reported. By contrast, 30-day readmission rates were not significantly different, at 27.4% and 26.8% for the minimally invasive and open approach, respectively 

Total Medicare payments within 90 days of surgery were significantly lower for minimally invasive versus open radical cystectomy, at $34,369 and $38,071, respectively, in adjusted multiple regression analysis 

Dr. Modi said it was somewhat surprising that 90-day episode spending was lower for the minimally invasive approach, given a previous analysis showing the opposite-that the minimally invasive approach was associated with higher 90-day spending 

That previous analysis focused on an earlier time period, 2002-2012-earlier in the adoption of minimally invasive technology-which could mean that higher spending was due to inexperience or more “cautious” postoperative management, Dr. Modi said.

Cystectomy best option for rare form of bladder Ca

Mortality outcomes of minimally invasive versus open radical cystectomy were not analyzed in the current study due to the short time frame evaluated, and oncologic outcomes were not available in the Medicare data, according to Dr. Modi.

“It’s possible that there are patient factors that we were unable to account for in our analysis, and so we wouldn’t make any strong claims about the effectiveness of robotic cystectomy based on this data,” he said. “A randomized trial really is the best way to answer those types of questions.”

Effectiveness of robotic cystectomy was the main focus of the randomized, phase III RAZOR trial. In the 

 report on the study, RAZOR investigators said robot-assisted radical cystectomy was noninferior to open radical cystectomy with regard to the clinical primary endpoint of progression-free survival.

Author | Andrew Bowser

Articles

Pembro shows promising antitumor activity

Pyruvate kinase appears to be bladder cancer marker

Routine PET/CT not beneficial for node-negative patients

Minimally invasive cystectomy linked with shorter hospital stay