Urothelial cancer, also known as transitional cell carcinoma, is most commonly found within the urinary system, where it can be found in the bladder, urethra, ureter, and the renal pelvis; however, it is most commonly located in the bladder. Urothelial cancer comprises nearly 90 percent of all bladder cancers and, of these, approximately 50 percent have an association with smoking. This cancer is particularly lethal if metastasis occurs. For patients having local lymph node metastases (i.e., in the surrounding tissues), the 5-year survival rate is approximately 35 percent. However, if there are metastases distant from the initial source, the 5-year survival rate plummets to 5 percent.
To address the unmet needs of patients with this invasive disease, Joaquim Bellmunt, MD, PhD, of the Dana-Farber Cancer Institute and Harvard Medical School, Boston, led the efforts for Keynote-045 (NCT02256436), an international open-label, phase III clinical trial that evaluated the use of pembrolizumab, an anti-PD-1 monoclonal antibody, versus the investigator's choice of taxane (docetaxel or paclitaxel) or vinflunine chemotherapy for the treatment of locally advanced or metastatic urothelial cancer patients who had recurrence or disease progression after platinum-based chemotherapy. A detailed report of data from this trial was published recently (N Engl J Med 2017;376:1015-1026).
“The current internationally-accepted standard first-line treatment for metastatic urothelial cancer is platinum-based combination chemotherapy,” Bellmunt noted. Those patients treated with cisplatin-based regimens have shown a median overall survival (OS) of 12-15 months, while those on carboplatin-based therapies have displayed a median OS of approximately 9 months. Bellmunt explained, “If these patients show disease progression after these therapies, there are currently no agreed-upon standard second-line therapies.
“Frequently, second-line therapy consisting of single-agent taxanes, such as docetaxel or paclitaxel, is used. Additionally, in Europe, vinflunine is the only agent EMA approved and being utilized for these patients.
“The median overall survival for metastatic urothelial cancer patients undergoing the currently available second-line chemotherapies is only 6-7 months, with a progression-free survival of 3 months, thus highlighting the need for an effective therapy for this group,” Bellmunt noted.
Given the need for effective second-line therapies for locally advanced or metastatic urothelial cancer patients and the success that had been displayed by pembrolizumab in the interruption of the PD-1/PD-L1 immunosuppressive interaction in a number of other oncological settings, this anti-PD-1 antibody was considered for the treatment of urothelial cancer patients.
In 2013, a phase 1b open-label clinical trial, KEYNOTE-012 (NCT01848834), was initiated and evaluated the use of pembrolizumab in a variety of solid tumor cancers, including urothelial cancer (Cohort C). Subsequently, in 2015, a phase II, open-label clinical trial, KEYNOTE-052 (NCT02335424), was initiated and assessed pembrolizumab as a first-line therapy in cisplatin-ineligible urothelial cancer patients.
In Cohort C of this multi-cohort, phase 1b clinical trial, cytologically- or histologically-confirmed urothelial cancer patients with locally-advanced or metastatic disease that had a combined positive score (CPS) of 1 percent or greater (i.e., 1% or more of their tumor and infiltrating cells expressed PD-L1 relative to the total number of tumor cells) were treated with 10 mg/kg pembrolizumab IV once every 2 weeks until progressive disease, unmanageable toxicity, or the end of the study (24 months). Assessment was performed by a central review committee using RECIST v. 1.1 criteria for solid tumors. The primary endpoints for this study were overall response (RECIST v. 1.1) and safety.
From May 2013 to December 2013, 115 locally advanced or metastatic urothelial cancer patients had tissue samples screened. PD-L1-positive results were obtained for 61 patients and, of these, 33 were enrolled in this study. Full analyses were performed for 27 patients; however, six of the enrollees were not assessable.
Overall response was noted for seven of the 27 (26%) assessable patients with a median follow-up period of 13 months. Complete response (CR) was obtained for three (11%) of the patients, while partial response (PR) was noted for four (15%). Stable disease was noted for four patients (15%), while 14 (52%) had disease progression as the best outcome. Data were unavailable for two patients. Observed response rates were higher and more durable compared than those observed with chemotherapy in this setting.
The most frequent treatment-related adverse events (AEs) noted were fatigue (six of 33 patients, 18%) and peripheral edema (four of 33, 12%). Of the 33 patients enrolled in the study, 20 (61%) experienced a treatment-related AE of any type, while 13 (39%) had no AE. There were 11 grade 3 treatment-related AEs in five different patients and five serious treatment-related AEs in three different patients. Six patients had an AE that resulted in treatment interruption. Although four deaths occurred during the trial, none were considered to be treatment-related. A detailed report of this study's findings has been published recently (Lancet Oncol 2017;18:212-220).
In this open-label, phase II clinical trial, pembrolizumab was assessed as a first-line therapy in cisplatin-ineligible advanced/unresectable or metastatic urothelial cancer patients. These patients were deemed cisplatin-ineligible if they met one or more of the following criteria: Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2; creatinine clearance of less than 60 mL/minute; grade 2 hearing loss or neuropathy; New York Heart Association Class III chronic heart failure. Participants in this study were dosed at 200 mg IV once every 3 weeks until disease progression, unacceptable toxicity, or end of therapy (24 months).
The primary endpoints for this study were independent review-confirmed RECIST v. 1.1 objective response rate (ORR) in all patients and in PD-L1 positive patients by CPS. A secondary endpoint was the determination of the PD-L1 high cutoff level (≥ 1% or ≥ 10%). An interim report was delivered for the first 100 participants in this study at the 2016 European Society for Medical Oncology conference (Annals of Oncology 2016; doi:10.1093/annonc/mdw435.25).
The ORR for all patients in this report (n=100) was 24.0 percent, and 6.0 percent showed CR. For patients having a CPS ≥ 1 percent (n=63), the ORR was 25.4 percent and 6.3 percent displayed CR. Better results were clearly obtained for those having a CPS of ≥ 10 percent (n=30); this group had an ORR of 36.7 percent while 13.3 percent showed CR.
Patient eligibility was limited to those having histologically- or cytologically-verified urothelial cancer of the bladder, renal pelvis, ureter, or urethra with predominantly transitional-cell histological features who had surgically incurable disease recurrence within 12 months after receiving platinum-based neoadjuvant or adjuvant chemotherapy (localized muscle invasive disease) or progression after platinum-based chemotherapy given for advanced disease. Inclusion criteria also included the receipt of two or fewer lines of systemic chemotherapy for advanced disease patients, a measurable tumor mass according to RECIST v. 1.1 criteria, an ECOG PS of 0-2. Patients having an ECOG PS of 2 were excluded from this study if they also met one or more of the following criteria: last chemotherapy dose < 3 months previously; liver metastases present; hemoglobin content < 10 g/dL. Additionally, those receiving previous checkpoint inhibitor therapy (anti-CTLA-4, anti-PD-1, or anti-PD-L1) were also excluded from this trial. ?Patients were randomized in an approximately 1:1 ratio to receive pembrolizumab (200 mg) or the investigator's choice of docetaxel (75 mg/m2), paclitaxel (175 mg/m2), or vinflunine (320 mg/m2), all with IV dosing once every 3 weeks (Q3W). Randomized patients were stratified according to the following criteria: ECOG PS (0 or 1 vs. 2); hemoglobin concentration (< 10 g/dL vs. ≥ 10 g/dL); liver metastases (present vs. not present), and time since last chemotherapy dose (< 3 months vs. ≥ 3 months). Treatment was continued until disease progression (RECIST v. 1.1-confirmed), unacceptable toxicity development, investigator-determined treatment cessation, consent withdrawal, or completion of 24 months of therapy. Patients who had disease progression but had clinically stable status were permitted to continue their therapy at the investigator's discretion. There was no crossover to the pembrolizumab group upon disease progression.
When asked about the objectives for this clinical trial, Bellmunt commented, “The primary endpoints for this study were OS and progression-free survival (PFS) in both the total patient population and in those who had CPS of 10 percent or greater.” Regarding the definitions used in this trial, Bellmunt clarified, “OS was defined as the time from randomization to death from any cause, while PFS was defined as the time from randomization until disease progression or death from any reason.”
OS and PFS were determined using Kaplan-Meier methodology. The secondary endpoints, the ORR, and CR/PR were assessed in both the total patient population as well as in those having a CPS of 10 percent or greater. Health-related quality of life (HRQoL) was also evaluated using a prespecified statistical analysis plan.
Of the 748 patients screened in this trial, 542 were randomized to either the pembrolizumab (n=270) or the chemotherapy (n=272) group. For the chemotherapy group, patients were divided fairly evenly between the different agents: docetaxel (n=84); paclitaxel (n=84); vinflunine (n=87). Regarding the patients in the study, Bellmunt noted, “The demographics and disease characteristics of these patients at baseline were fairly balanced between the two treatment groups.”
The median follow-up duration was 14.1 months (time from randomization to data cutoff, Sept. 7, 2016), while the median study treatment duration was 3.5 months (range - < 0.1-22.1 months) for the pembrolizumab group and 1.5 months (range - < 0.1-14.2 months) for the chemotherapy group, respectively. At the date of cutoff, 49 patients in the pembrolizumab group and three in the chemotherapy group were still receiving study treatments.
The median OS for the total patient population was 10.3 months (95% CI–8.0-11.8 months) for the pembrolizumab group and 7.4 months (95% CI–6.1-8.3 months) for the chemotherapy group. As a result, the hazard ratio (HR) for death was 0.73 (95% CI–0.59-0.91; P=0.002).
When the OS values were assessed in those having CPS of 10 percent or higher, an even sharper difference was noted. For those patients in the pembrolizumab group, the median OS was 8.0 months (95% CI–5.0-12.3 months), while for the chemotherapy group, this figure was 5.2 months (95% CI–4.0-7.4 months). This afforded an HR for death of 0.57 (95% CI–0.37-0.88; P=0.005).
There were a total of 437 incidences of death or disease progression in the total intent-to-treat population. Notably, there was no significant difference for the median PFS between the pembrolizumab (2.1 months; 95% CI–2.0-2.2 months) and the chemotherapy (3.3 months; 95% CI–2.3-3.5 months) groups, which is shown by the HR for death or disease progression (0.98; 95% CI–0.81-1.19; P=0.42). The 12-month estimated PFS rate was 16.8 percent (95% CI–12.3-22.0%) for the pembrolizumab group and 6.2 percent (95% CI–3.3-10.2%) for the chemotherapy group. Interestingly, for the patients having CPS of 10 percent or greater, the values were fairly similar, with an HR for death or disease progression of 0.89 (95% CI–0.61-1.28; P=0.24).
There was a significant difference in the median ORRs for the pembrolizumab group (21.1%; 95% CI–16.4-26.5%) and the chemotherapy group (11.4%; 95% CI–7.9-15.8%), although the time to response was the same for both groups, 2.1 months. The median duration of response was not reached for the pembrolizumab group (range: 1.6+-15.6+ months and was 4.3 months (range: 1.4+-15.4+ months) for the chemotherapy groups. Many patients exhibited ongoing responses at the time of data cutoff. As of Sept. 7, 2016, 41 of the 57 responding patients in the pembrolizumab group (72%) had ongoing responses, while for the chemotherapy group 11 of 31 showed continued response (35%). Additionally, 36 of the pembrolizumab (63%) and two of the chemotherapy-responding patients (6%) had continuing treatment at data cutoff.
“The responses obtained with pembrolizumab tended to be strong, durable, and persistent responses; it is even possible there could be persistent immunological memory in these patients,” Bellmunt commented.
There were considerably fewer treatment-related AEs in the pembrolizumab group (60.9% of patients) than in the chemotherapy group (90.2% of patients). There were four treatment-related deaths for the pembrolizumab group, one each for pneumonitis, malignant neoplasm progression, urinary tract obstruction, and unspecified cause. There were also four treatment-related deaths in the chemotherapy group, two from sepsis, one from septic shock, and one of unspecified cause. Pembrolizumab was associated with substantially better HRQoL than investigator's choice of paclitaxel, docetaxel, or vinflunine. “Broadly speaking, the side effects were milder and the general quality of life was better for patients in the pembrolizumab group,” explained Bellmunt.
“The general benefit for pembrolizumab versus chemotherapy was apparent across both the total patient population and those having CPS of 10 percent or more,” Bellmunt noted. “Interestingly, the benefit for pembrolizumab appeared to be independent of PD-L1 expression levels on the tumor and infiltrating cells. However, there appeared to be a benefit for pembrolizumab treatment for those that were smokers, possibly as a result of their tendency to have a higher mutational load.”
Summarizing the results for the study, Bellmunt concluded, “Pembrolizumab clearly offered an advantage relative to the chemotherapy treatments tested. The most encouraging aspect of this trial was the responses observed in the pembrolizumab group, which tended to be rather robust and long-lived, possibly indicating immunological memory. Given the positive results seen in KEYNOTE-045 for this difficult disease, pembrolizumab is now being evaluated for treatment at earlier and less advanced stages of urothelial cancer.”
Richard Simoneaux is a contributing writer.