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ICIs for NeoAdj Bladder Cancer Tx
Neoadjuvant ICI Therapy for Bladder Cancer: My Thoughts on Where We Stand Today

Released: September 10, 2018

Expiration: September 09, 2019

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The standard of care for eligible patients with muscle-invasive bladder cancer is neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy. Clinical experience, including randomized phase III trial findings, show that this produces pathologic CR rates of 30% to 40%, with an absolute improvement in survival of approximately 5%. Prospective, randomized studies, including individual patient data, show that a pathologic CR (pT0) to cisplatin-based chemotherapy is associated with excellent survival outcomes.

Unfortunately, up to one half of patients with bladder cancer are not candidates for cisplatin-based chemotherapy because of coexisting medical problems. So, although it is important to try to improve pathologic CR rates in those patients who are treated with cisplatin-based combination chemotherapy, it is also imperative to find improved neoadjuvant strategies for patients who are ineligible for cisplatin. At the 2018 ASCO annual meeting, 2 promising studies of neoadjuvant checkpoint inhibitor regimens for the treatment of bladder cancer were presented.

PURE-01: Neoadjuvant Pembrolizumab
Interim results were presented from the phase II PURE-01 study, in which patients with muscle-invasive bladder cancer received 3 cycles of neoadjuvant pembrolizumab, a PD-1 antibody. In this study, patients (N = 43 to date) had at least 50% urothelial carcinoma histology with a clinical stage less than or equal to T3bN0. Residual disease after transurethral resection of their bladder tumor was required for enrollment, as a successful transurethral resection of the bladder tumor can achieve a pathologic CR in approximately 15% of patients. The patients were otherwise eligible for cisplatin chemotherapy, and there was a provision such that additional dose-dense MVAC for 4 cycles could be administered in patients not responding to pembrolizumab therapy. The primary endpoint was pathologic CR in the intent-to-treat population. The study also included an exploratory biomarker analysis of response to pembrolizumab, including PD-L1 expression by IHC, next-generation sequencing, and a 22-gene T-cell–inflamed signature identified by quantitative PCR. The majority of patients (~ 60%) had clinical T3 disease, and the median time from discontinuation of pembrolizumab to radical cystectomy was 22 days.

Pembrolizumab was well tolerated; 1 patient discontinued due to a grade 3 elevation of alanine aminotransferase. Notably, the pathologic CR rate was approximately 40%, and more than 50% of patients were able to be pathologically downstaged to less than T2—these are very promising results compared with cisplatin-based combination chemotherapy. The biomarker analysis suggested an improved pathologic CR rate in patients with a median PD-L1 combined positive score (CPS) of at least 20% or genomic alterations in DNA damage repair genes or RB1. In patients with both biomarkers, the pathologic CR rate was 90%. Granted, only 10 patients had that specific profile, but this result highlights the potential ability to use biomarkers to select patients who may not need a radical cystectomy.

In addition, analyses in 18 patients showed that the PD-L1 CPS percentage increased and the median tumor mutational burden levels decreased following pembrolizumab and that, in patients who did achieve a pathologic CR, there were significantly higher expression levels of genes associated with T-cell inflammatory signatures. These are very intriguing data that suggest that checkpoint inhibitors are influencing the immune tumor microenvironment.

ABACUS: Neoadjuvant Atezolizumab
Also presented were interim results from the phase II ABACUS study of neoadjuvant atezolizumab, a PD-L1 antibody. In this clinical trial, cisplatin-ineligible patients (N = 68) with T2-T4aN0M0 bladder cancer with transitional histology and residual disease received 2 cycles of atezolizumab followed by surgery. The coprimary endpoints were pathologic CR in at least 20% and an increase in CD8+ cell counts. A secondary endpoint was radiologic response.

Two cycles of atezolizumab was very well tolerated, with few grade 3/4 adverse events; only 8 patients had drug-related adverse events that prevented a second cycle. As in PURE-01, the pathologic CR rate was promising: 29% overall and 40% in the PD-L1–positive population (n = 10/56). Results also showed that treatment with atezolizumab increased the percentage of PD-L1–positive patients from 35% to 73% and increased CD8+ cell counts as well. In addition, radiologic responses were seen on imaging in 28% of patients.

Of note, the methods for PD-L1 biomarker testing differ with pembrolizumab and atezolizumab. The PD-L1 biomarker assay in PURE-01 uses the murine 22C3 antibody to determine a combined positive score (CPS) of the ratio of PD-L1–expressing tumor-infiltrating immune cells relative to the total number of tumor cells in a biopsy. The SP142 PD-L1 assay used in ABACUS determines the percentage of positive tumor-infiltrating cells in the tumor area, with PD-L1 positivity defined as at least 5%.

Moving Forward Cautiously
Both studies currently have only interim analyses of data available, and we await the full data presentations. That said, these phase II findings are promising and speak to the potential activity of monotherapy with immune checkpoint inhibitors in patients with muscle-invasive bladder cancer. However, in his discussion of these abstracts at ASCO 2018, Matthew Galsky, MD, specifically cautioned people in terms of interpreting pathologic CR and associations with long-term outcomes on a trial level vs an individual patient level—we do not yet know whether the pathologic CRs seen in these trials translate to survival improvements. Although these trial data represent an interesting new potential neoadjuvant treatment strategy for our patients, we still need randomized phase III data to make changes to our current paradigm.

At the University of North Carolina, we are conducting a phase II study of pembrolizumab in combination with gemcitabine/cisplatin as neoadjuvant therapy prior to radical cystectomy in patients with muscle-invasive bladder cancer (planned N = 39). The trial includes a series of very exciting, embedded correlative translational science endpoints in addition to the primary endpoint of pathologic response.

Multiple studies of regimens combining chemotherapy with immune checkpoint blockade in patients with muscle-invasive bladder cancer are also ongoing. It is hoped that the survival improvements seen in other settings, such as in non-small-cell lung cancer with pembrolizumab plus pemetrexed and a platinum-based drug, will be evident in bladder cancer as well. Another as-yet-unanswered question is how many additional cycles of immune checkpoint inhibition are needed in the neoadjuvant setting.

Have you begun using checkpoint inhibitors to treat patients with bladder cancer? Share your experiences in the comment box below.
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