Standard chemoradiation therapy regimens have had marked success for patients with muscle-invasive bladder cancer; however, up to 30% of patients who receive treatment with bladder preserving intent will have recurrence.
For patients with muscle-invasive bladder cancer (MIBC) who desire to pursue bladder preserving approaches to care, chemoradiation therapy (CRT) is the recommended approach across guidelines.1,2 Standard CRT regimens have had marked success for patients with MIBC; however, up to 30% of patients who receive treatment with bladder preserving intent will have recurrence.2
An unanswered question for patients with MIBC is the identification of an optimal CRT regimen. Following transurethral resection of a bladder tumor (TURBT), the recommended chemotherapy backbones for CRT from the National Comprehensive Cancer Network guidelines include 5-fluorouracil (5-FU) plus mitomycin, cisplatin either alone or in combination with 5-FU or paclitaxel, and low-dose gemcitabine.1 Additionally, the standard doses of radiation therapy are 1.8-2.0 Gy daily fractionation.
Approaches to build on investigator’s choice of CRT look to leverage immunotherapy, the first choice of which is the anti–PD-1 agent, pembrolizumab (Keytruda) which has demonstrated efficacy as a treatment prior to radical cystectomy in patients with MIBC. Specifically, in data from a phase 2 study (NCT02736266) evaluating single-agent neoadjuvant pembrolizumab, tumor downstaging to p1 or lower was observed among 55% (95% CI, 46%-65%) of the 114 treated patients.3
Synergistic effects of anti–PD-1 blockade with chemotherapy and radiotherapy, respectively, have been reported.4 Investigators have undertaken efforts to demonstrate that this efficacy and tolerability extends to CRT.5,6
In ANZUP 1502 (NCT02662062) a phase 2 trial of pembrolizumab (Keytruda) in combination with CRT in patients with MIBC who have undergone maximally resection with TURBT electing for bladder preservation or are unable to undergo cystectomy. Among the first 10 patients who received treatment the complete response rate at week 31 was 90%.5 Investigators also noted a manageable safety profile with the combination with urinary frequency, hematuria, anemia, urinary sepsis, and hypertension reported as the only grade 3 adverse effects (AEs). Additionally, no grade 3 or 4 immune-related toxicities were reported.
Further, data from a phase 2 trial (NCT02621151) of pembrolizumab, gemcitabine, and concurrent hypofractionated radiation therapy showed promising efficacy in both the safety and efficacy populations.6 Notably, among the 6 patients enrolled to the safety cohort, the complete response rate was 83% with 1 patient not evaluable due to missed cytology or biopsy. Additionally, in the safety cohort, 1 patient experienced dose-limited toxicity that was immune related (grade 2 diarrhea) that was treated with corticosteroids. Among the 48 patients enrolled to the phase 2 efficacy cohort, 85% completed therapy.6
In results presented at the 2021 American Society of Clinical Oncology Annual Meeting, lead study author Arjun Vasant Balar, MD, noted differences in primary end point efficacy based on the definitions in the protocol. “Per protocol, the definition for post–radiation therapy response required [all] patients to get a cystoscopy, [transurethral resection] biopsy of the tumor site, and cytology. If you missed any 1 of those, then [the patient] was not evaluable.” The CR rate for patients who met the criteria was 56%, with a partial response rate of 8.3%. One patient had disease progression and 10 were not evaluable.6
“[Approximately 11 out of the total 54 [patients] were not evaluable for this primary end point because they had a visibly normal cystoscopy, a cytology was normal,” Balar said, adding that in clinical practice those with those who present with those 2 components would be considered clinical CRs. “When we look at it this way, it’s encouraging to see that [nearly] 80% of patients in the intention-to-treat study population had clinical CRs,” he said.
Specifically, 77% of patients had a recorded CR with 8.3% maintaining a partial response. When combined with the safety population (n = 54) the CR rate was 80%. In terms of the dual primary end point of bladder-intact disease-free survival the estimated 1-year rate was 88% (95% CI, 73%-95%) at a median follow-up of 14.6 months (range, 1.6-32.3). In a key secondary end point analysis, among all-treated patients in both cohorts the estimated 1-year metastis-free survival (MFS) rate was 85% (95% CI, 71%-93%).6
Balar noted that the immune-related toxicities that were observed were resolved with corticosteroids. “Bladder preservation therapy is an effective nonsurgical option for patients with MIBC and with curative intent,” he said. “Pembrolizumab, when added to this therapy, specifically with hypofactionated radiation treatment and twice-weekly gemcitabine, is safe. It’s well tolerated and there is promising efficacy in this early analysis.”
Building on these findings, investigators have initiated a phase 3 trial to further evaluate and better define the role a trimodality approach may have in the treatment landscape for these patients.
In the phase 3 KEYNOTE-922 trial (NCT04241185), investigators will randomly assign up to 636 patients with MIBC to CRT with or without pembrolizumab.7 The radiation therapy will be administered as either conventional schedule of 64 Gy administered to the individual’s bladder or bladder and pelvic nodes with 32 fractions administered over 6.5 weeks. Participants could also receive hypofractionated radiotherapy, which would consist of 55 Gy of radiation administered to the bladder with 24 fractions administered over 4 weeks. Chemotherapy options include cisplatin, 5-FU, mitomycin, or gemcitabine.7
Patients who are assigned to the investigative arm will receive pembrolizumab at 400 mg intravenously once every 6 weeks. Treatment will continue with pembrolizumab or placebo for up to 9 doses.7,8
Investigators will stratify patients by ECOG status, PD-L1 combined score (< 10 vs ≥ 10), tumor stage, and geographic region (US vs Europe vs all other locations).8
The primary end point of the trial is bladder intact event-free survival which will be noted as an occurrence of any of the following: residual or recurrent MIBC following completion of CRT, detection of nodal or distant metastases via CT and CT urography or magnetic resonance urography per blinded independent central review. Additionally, assessments may be evaluated by biopsy results assessed by central pathology review, occurrence of radical cystectomy, or death due to any cause. If biopsy is not obtainable, study protocol states that imaging will be sufficient for analysis. The analyses will occur 10 weeks after CRT, then every 12 weeks until the end of year 12, and once every 24 weeks thereafter.7,8
Secondary outcome measures include overall survival, MFS, time to occurrence of non-MIBC, and safety including incidence of AEs, discontinuation rates due to AEs, and quality-of-life surveys.7
In terms of eligibility for the trial, protocol states that patients must have MIBC that is not metastatic (N0M0) and has planned CRT that is inclusive of one of the protocol-specified radiosensitizing chemotherapy regimens. Additionally, individuals must have an ECOG performance status of 0, 1, or 2, and adequate organ function. Of note, those who have received prior therapy with an anti–PD-1, anti–PD-L1, or agent directed at a stimulatory or coinhibitory T-cell receptor are not eligible for enrollment.7