Clinical Trials Corner

Dear Readers,

The Clinical Trials Corner of the Bladder Cancer Journal is a section devoted towards highlighting ongoing trials or recently completed trials in urothelial cancer. Our hope is to encourage accrual for ongoing trials and to educate readers on the results of completed trials. If you feel that you would like to draw attention to a specific trial, please feel free to email us at: pkagarwal@uchicago.edu and/or cns9006@med.cornell.edu.

Sincerely,

Piyush K. Agarwal Cora N. Sternberg
Piyush K. Agarwal, MD Cora N. Sternberg, MD, FACP
Associate Editor, Bladder Cancer Associate Editor, Bladder Cancer
Director, Bladder Cancer Program Clinical Director, Englander Institute of Precision Medicine
University of Chicago Medicine Weill Cornell Medicine
Chicago, IL, USA New York, NY, USA

A Phase III, Open-Label, Multicenter, Randomized Study of Atezolizumab (Anti-PD-L1 Antibody) Versus Observation as Adjuvant Therapy in Patients With High-Risk Muscle-Invasive Urothelial Carcinoma After Surgical Resection.

Sponsor: 
Hoffmann-La Roche
Enrollment: 
809
Study Design: 
This is a phase III, multicenter open-label trial that randomly assigned patients with muscle-invasive urothelial cancer after surgical resection with high risk features for recurrence to either observation or adjuvant atezolizumab treatment in a 1:1 fashion. Patients randomized to intravenous atezolizumab received therapy with 1200 mg every 3 weeks for up to 16 cycles. Patients with pT2-T4 disease after neoadjuvant chemotherapy, or pT3-4 disease without neoadjuvant chemotherapy, or any node positive disease after radical cystectomy were considered high risk for recurrence and eligible for the trial. Assessment of tumor status was performed by radiographic imaging prior to initiation of treatment.
Rationale: 
Patients with high-risk muscle invasive urothelial cancer after surgical resection have limited options for treatment. Historically, they have been observed only to later develop local or systemic recurrences and to eventually succumb to urothelial cancer. However, with the absence of a proven benefit of adjuvant therapy and dearth of treatments except for chemotherapy, there has been little progress in this disease space of urothelial cancer. This trial, also known as the IMvigor010 trial, aimed to evaluate the impact of adjuvant atezolizumab, a PD-L1 inhibitor, in patients randomized to receiving such therapy after radical cystectomy with high risk features seen on pathology.
Endpoints: 
Primary outcome was disease-free survival (DFS) from the time of randomization and included pelvic (local) recurrence, extravesical urinary tract recurrence, distant metastases, or death from any cause. Secondary outcomes included overall survival, disease-specific survival, disease metastasis-free survival, and non-urinary tract recurrence-free survival.
Comments: 
This trial unfortunately did not demonstrate a difference in DFS with the use of adjuvant atezolizumab. One of the criticisms is that this trial may have excluded patients likely to benefit and included patients unlikely to benefit with atezolizumab. Patients with positive surgical margins are most likely to recur with local (pelvic) recurrence and may benefit most from adjuvant therapy but were excluded from this trial. Another potential issue is potentially that there may be a difference in efficacy between PD-1 and PD-L1 inhibitors as PD-1 inhibitors have demonstrated slightly better survival results in some studies although no studies have directly compared these two different types of inhibitors.
Results: 
In this trial, Atezolizumab failed to meet the primary end point, disease-free survival (DFS), as adjuvant monotherapy in patients with muscle-invasive urothelial cancer (MIUC) compared with observation in the phase III IMvigor010 clinical trial, according to a press release from Roche, developer of the drug on January 24, 2020 (https://bit.ly/38zdRoE)

A Phase II Clinical Trial to Study the Efficacy and Safety of Pembrolizumab (MK-3475) in Subjects With High Risk Non-muscle Invasive Bladder Cancer (NMIBC) Unresponsive to Bacillus Calmette-Guerin (BCG) Therapy

Status: 
Recruiting
Sponsor: 
Merck Sharp & Dohme Corp
Enrollment: 
260
Study Design: 
This is a phase II, multicenter trial for patients with high risk NMIBC (T1, CIS, and/or high-grade Ta) who are deemed BCG-unresponsive after adequate BCG therapy who are either unfit or refuse radical cystectomy. This was a single-arm study in which all patients were treated with intravenous pembrolizumab, 200 mg, every 3 weeks until recurrence of high-risk disease or unacceptable toxicity for up to 24 months. Assessment of tumor status was performed by cystoscopy and cytology and for cause biopsies every 3 months.
Rationale: 
PD-L1 and PD-1 inhibitors are now established treatments both for 1st line treatment of patients with locally advanced or metastatic bladder cancer that are cisplatin-ineligible or experiencing disease progression after platinum-based chemotherapy. Recently, data from 2 small phase II trials suggest their potential efficacy when given as neoadjuvant therapy prior to radical cystectomy. Several ongoing trials have also evaluated this immunotherapy in the treatment of BCG-unresponsive NMIBC. This trial by Merck Sharp & Dohme specifically evaluated the safety and efficacy of its PD-1 inhibitor, pembrolizumab, in the treatment of patients with BCG-unresponsive non-muscle invasive bladder cancer (NMIBC) given the already encouraging results in other disease states of urothelial cancer (neoadjuvant prior to cystectomy and metastatic).
Endpoints: 
Primary outcomes were complete response rate and disease-free survival rate. Complete response rate (CR) was defined by a negative cystoscopy or bladder biopsies performed for an abnormal cystoscopy, negative urine cytology, and normal CT urogram. Secondary outcome was duration of response.
Comments: 
This trial led to the approval of pembrolizumab in patients with BCG-unresponsive CIS. Although this is a valuable advance in the treatment of NMIBC, it does raise several potential concerns. Will this be used as first line therapy for patients with BCG unresponsive disease or will urologists choose alternative intravesical therapies such as gemcitabine/docetaxel. Two other intravesical therapies, vicinium and adenoviral mediated interferon mediated gene therapy, are currently under review by the FDA. The cost of immunotherapy will raise the cost of bladder cancer care astronomically imploring us to evaluate whether such treatment justifies the cost. This is especially sobering when one considers that on follow-up, only 19% of the entire cohort of CIS-treated patients continued with a CR of at least one year begging the question whether this is an appropriate benchmark for new therapies in the BCG-unresponsive disease state.
Results: 
At the time of analysis, the trial enrolled 148 patients of whom 96 patients had BCG-unresponsive CIS either with or without papillary tumors. The 3-month CR rate in the 96 patients with CIS was 41% (95% CI: 31-51) and the median duration of response was 16.2 months (range 0-30.4 months). Among the 39 patients with a CR, 18 (46%) and 19% among all patients with CIS maintained a CR of at least 12 months after starting treatment [Reference: fda.gov 1/8/2020]. The safety profile was in line with other PD-1 inhibitor studies, however, 99 patients experienced 1 or more adverse events (AEs) and treatment-related AEs were seen in up to 65.7% of patients. Although grade 3-5 AEs were only seen in 29.4% of patients, two patients died while on therapy during the course of the trial, but only one of these deaths was deemed to be immune-related.

Initial Results From TROPHY-U-01: A Phase 2 Open-Label Study of Sacituzumab Govitecan in Patients with Metastatic Urothelial Cancer (mUC) After Failure of Platinum-Based Regimens or Immunotherapy

Sponsor: 
Immunomedics, Inc
Enrollment: 
100
Study Design: 
TROPHY-U-01. SG 10 mg/kg was given on days 1 and 8 every 21 days. Data on Cohort A in 35 of 100 pts with mUC who progressed after prior platinum-based and checkpoint inhibition was presented.
Rationale: 
Pts who progress after platinum-based therapy or who don’t respond or don’t tolerate immunotherapy have limited treatment options and poor outcomes. Unfortunately, checkpoint inhibitors are ineffective for a majority of pts. Additional treatment options are needed. Sacituzumab Govitecan (SG) is a Trop-2-Directed Antibody-Drug Conjugate (ADC). Trop-2 is an epithelial cell surface antigen highly expressed in UC and a wide range of epithelial cancers. SG is distinct from other ADCs, with a high drug-to-antibody ratio. Linker hydrolysis releases the cytotoxic SN-38 in tumor tissue (intracellularly and in the tumor microenvironment. The payload for SG is SN-38, a Topo1 inhibitor and more potent active metabolite of irinotecan.
Endpoints: 
The primary objective was overall response rate (ORR). Secondary objectives included. safety/tolerability, duration of response (DOR), progression-free survival (PFS) and overall survival (OS).
Comments: 
Antibody-Drug Conjugates are increasing of interest in the treatment of mUC. These data demonstrate that SG has the potential to change the treatment landscape of mUC.
Results: 
35 pts included in the interim analysis received ≥1 cycle of study treatment and had ≥1 on-treatment response assessment. The ORR was 29% (2 CR, 6 PR, 2 additional PRs pending confirmation). ORR was 25.0% in pts with liver metastases. 74% of pts demonstrated a reduction in tumor size at a median follow-up of 4.1 mos. 57% of pts are continuing treatment. SG was well tolerated, with a manageable, predictable, and consistent safety profile, with neutropenia and leukopenia as the main toxicities. Diarrhea and fatigue were observed.

EV-103: Initial results of Enfortumab Vedotin plus Pembrolizumab for locally advanced or metastatic urothelial carcinoma (mUC)

Sponsor: 
Astellas Pharma Inc, in collaboration with Seattle Genetics
Enrollment: 
45
Study Design: 
This study examined the safety and anticancer activity of EV IV as monotherapy and in combination with other anticancer therapies in UC. The study will be conducted in multiple parts: dose escalation (enfortumab vedotin + pembrolizumab) and dose expansion (cohorts of enfortumab vedotin + pembrolizumab and/or chemotherapy) for locally advanced and metastatic UC and EV alone and in combination with pembrolizumab in patients with earlier stage of the disease (muscle invasive UC).
Rationale: 
There is a major unmet medical need for patients with mUC for whom available therapies have failed the patients. Antibody-drug conjugates (ADCs) are monoclonal Abs conjugated to cytotoxic drugs or a radionucleotide. This improves the potency and effectiveness of mAbs, allows for targeted delivery of a toxic payload to tumor cells, thereby minimizing non-specific, systemic toxicity. Enfortumab Vedotin (EV) is an ADC (anti-nectin 4 monoclonal Ab) linked to monomethyl auristatin E (MMAE) with evidence of induction of immunogenic cell death (ICD) in pre-clinical and in vitro data. MMAE disrupts microtubules resulting in ICD. EV showed an ORR of 45% in pts with prior PD-1/L1 inhibitors in a phase 1 study. In a single arm phase II trial (EV-201), single agent EV in pts previously treated with platinum and immune checkpoint inhibitors (NCT03219333) produced a 44% RR (12% CR; 32% PR) in 125 pts. The rationale for combining EV and an immune check point inhibitor such as pembrolizumab (pembro) stems from the fact that ICD releases innate immune activating molecules resulting in APC activation and presentation of tumor antigens to T cells. T cells mount antigen – specific response potentially augmented by PD-1/L1 inhibitors.
Endpoints: 
The primary goal of the study is to determine the safety, tolerability, and efficacy of EV alone and in combination with pembro and/or chemotherapy
Comments: 
EV alone had a high RR, but this study demonstrated that the combination of EV and immunotherapy with pembro has an even higher RR and is likely to become an important option in the first line setting for cisplatin ineligible pts in the treatment of mUC.
Results: 
EV and pembro in cisplatin ineligible 1st line or second line therapy results were reported in 45 pts. The ORR was 71% with 13% CR and 58% PR with rapid responses in 91% at first assessment.

IMvigor130: a phase III study of atezolizumab with or without platinum-based chemotherapy in previously untreated metastatic urothelial carcinoma (mUC)

Sponsor: 
Hoffmann-La Roche
Enrollment: 
1213
Study Design: 
IMvigor130 is an international phase III trial for pts with locally advanced or mUC who had not received prior systemic therapy. Pts had an ECOG PS ≤2 and were eligible for platinum-based therapy in the 1st line setting. Pts were stratified by PD-L1 IC status (IC0 vs IC1 vs IC2/3), Bajorin risk factor score including KPS <80% versus ≥80%, the presence of visceral metastases and investigator’s choice of chemotherapy. Pts were randomized 1:1:1 to receive atezo and platinum-based therapy (cisplatin or carboplatin) plus gemcitabine (arm A; n = 451), atezo monotherapy (arm B; n = 362), or placebo plus platinum-based therapy and gemcitabine (arm C; n = 400).
Rationale: 
Cisplatin-based chemotherapy has been standard first (1st) line treatment in mUC for > 30 years. Approximately 50% of patients (pts) with mUC are ineligible for cisplatin, and they generally receive inferior carboplatin-based regimens. PD-L1 and PD-1 inhibitors are the 1st new systemic therapies for mUC, both for 1st line treatment of cisplatin-ineligible pts and for pts experiencing disease progression despite platinum-based chemotherapy. The final PFS and interim OS results for IMvigor130, assessing atezolizumab (atezo) alone or in combination with gemcitabine and carboplatin or gemcitabine and cisplatin in 1st line mUC were presented.
Endpoints: 
The co-primary endpoints were investigator-assessed PFS and OS in arm A vs. arm C, and OS in arm B vs. arm C using a hierarchical approach. Key secondary endpoints included investigator-assessed overall response rate (ORR), duration of response, PFS and OS in arm B vs. arm C in the PD-L1 IC2/3 subgroup, and safety.
Comments: 
Whether the addition of immunotherapy to chemotherapy can improve outcomes in pts with mUC is an important question. IMvigor130 is the first trial to evaluate the combination of immunotherapy and chemotherapy in pts with mUC who are eligible and ineligible for chemotherapy. This trial represents the first positive signal in terms of PFS and a trend in OS. The results from IMvigor130 support atezo + platinum plus gemcitabine as an important new treatment option for patients with untreated mUC. Other similar trials are ongoing with other immunotherapeutic check point inhibitors.
Results: 
In the intent-to-treat population, the median OS with atezo and platinum plus gemcitabine was 16 months versus and 13.4 months for chemotherapy and placebo (HR, 0.83 (95% CI, 0.69, 1.00). When stratified by PD-L1 expression, pts with PD-L1–positive tumors (IC2/3) had an improvement in OS when treated with single-agent atezo compared with chemotherapy and placebo (HR, 0.68; 95% CI, 0.43-1.08). Median OS with the PD-L1 inhibitor was not estimated and was 17.8 mos. with chemotherapy. Follow-up of OS will be continued.

A Phase 3 Multicenter Trial Evaluating the Efficacy and Safety of UGN-101 on Ablation of Upper Urinary Tract Urothelial Carcinoma (OLYMPUS Study)

Sponsor: 
UroGen Pharma Ltd
Enrollment: 
71
Study Design: 
This was a Phase III multicenter, single-arm study evaluating the efficacy, safety, and tolerability of UGN-101 in the treatment of low-grade, non-invasive upper tract urothelial cancer. Patients had to have at least one lesion measuring between 5 and 15 mm left in place prior to treatment on this trial. Patients were treated by six weekly instillations of UGN-101 via a retrograde injection through a ureteral catheter and then evaluated 4-6 weeks after the last instillation.
Rationale: 
Upper tract urothelial cancer is difficult to treat given its relative scarcity compared to bladder urothelial cancer and the difficulties in delivering effective instillation of treatment within the upper urinary tract. UGN-101 is a novel investigational formulation of mitomycin C (MMC) admixed with a reverse thermal hydrogel that can be instilled as a liquid but that solidifies into a gel at body temperature. This allows for longer exposure of the urinary tract to MMC. Therefore, UGN-101 is an attractive agent for upper tract urothelial cancer that is unresectable and at high risk of recurrence.
Endpoints: 
The primary endpoint was a complete response (CR) rate defined as the percent of patients who achieved CR at the primary disease evaluation (PDE) visit which occurred on average at 11 weeks following initiation of treatment. The PDE consisted of ureteroscopy with biopsy of any remaining tumor and urine cytology. Patients who achieved CR at PDE were then treated once monthly with a maintenance regimen of UGN-101 for up to an additional 11 months or first recurrence.
Comments: 
This trial is trailblazing as it represents the first phase III trial in upper tract urothelial cancer. Furthermore, it demonstrates the tumor-ablative capacity of UGN-101 especially in patients deemed to be unresectable endoscopically at the start of the trial. Although serious side effects were seen, the mean age of patients was approximately 71 years and the fatal events were not deemed to be related to UGN-101. Furthermore, the side effects of ureteral narrowing and stricture could also have been due to the natural history of the disease and so without a comparator control group, it is hard to know if an observation cohort would have had the same side effects or not.
Results: 
The trial successfully enrolled 71 patients. Forty-two (59%) of the patients achieved a CR at the PDE visit. Of the 71 patients, 34 (48%) were deemed to have unresectable disease by their treating urologist and 19 (56%) of these “unresectable” patients achieved CR at the PDE visit. At 6 months of follow-up, 85% of evaluable patients with unresectable disease and 89% overall remained disease-free. The most common treated-related adverse events (AEs) were urinary tract infections, ureteral narrowing, and ureteral stricture formation. However, most of these were characterized as mild and resolved on follow-up.

QUILT-3.032: A Multicenter Clinical Trial of Intravesical Bacillus Calmette-Guerin (BCG) in Combination With ALT-803 in Patients With BCG Unresponsive High Grade Non-Muscle Invasive Bladder Cancer (NMIBC)

Status: 
Recruiting
Sponsor: 
Altor BioScience
Enrollment: 
160
Study Design: 
The Phase II single-arm multicenter trial targeted BCG unresponsive high grade NMIBC patients who refused radical cystectomy. Two cohorts were enrolled: cohort A included patients with CIS with or without Ta or T1 tumors while cohort B only had Ta and/or T1 disease. Patients were then treated with intravesical N-803 + BCG in an induction schedule of weekly treatments for 6 weeks. At 3 months, patients were re-evaluated by cystoscopy and biopsy and either treated with a second induction course or a 3-week maintenance course consisting of weekly treatments for 3 weeks. Maintenance courses continued at 6, 9, 12, and 18 months for eligible patients.
Rationale: 
N-803 (also known as ALT-803) is an IL-15 immunostimulatory protein complex (IL-15RαFc) that can promote activation and proliferation of NK (natural killer) cells and CD8+ T cells without recruiting regulatory T cells. It was initially evaluated in a phase Ib trial as an intravesical agent in combination with BCG (NCT02138734) for BCG-naïve patients. Remarkably, all patients on the trial remained disease-free at 24 months; however, as a single arm study, the responses could have been due to the BCG. Therefore, a randomized trial is underway in BCG-naïve patients. In preclinical experiments, the combination of N-803 and BCG reduced tumor burden and recruited cytotoxic T lymphocytes. This led to the combination of intravesical N-803 and BCG being evaluated in BCG unresponsive, high grade NMIBC. Initial findings of this study were just reported at the AUA annual meeting.
Endpoints: 
The primary endpoint was complete response (CR) rate of CIS at any time point in cohort A and the disease-free rate at 12 months in cohort B.
Comments: 
This trial is limited for many reasons mainly because this is an early analysis with accrual still ongoing and analysis being limited to few patients. Nevertheless, important takeaways from this interim analysis are that 1) CIS patients had a high CR rate (with some CRs as long as 12-18 months) and 2) patients with papillary only disease had a 77% 6-month disease-free survival rate. CIS is historically difficult to treat when unresponsive to BCG and so the high CR rate in cohort A is extremely encouraging. Furthermore, the use of intravesical N-803 in combination with BCG may emerge to be a less toxic, less cumbersome, and less costly approach to BCG unresponsive disease than systemic immunotherapies that are now under evaluation.
Results: 
62 patients have been enrolled to date on this trial with 35 patients with CIS (cohort A) and 27 patients with papillary tumor only (cohort B). In cohort A, of 18 evaluable patients, 16 (89%) have achieved CR. In cohort B, of 13 evaluable patients, 10 (77%) demonstrated no disease at their 3-month and 6-month assessment. Of the 8 patients evaluated beyond this time point, no recurrences have been noted. Three treatment-related adverse events (AEs) were reported (infection, anemia, and bacteremia) ranging grades 2-3. None of the patients experienced immune-related AEs.

A Phase 2, Randomized, Open Label, Parallel Arm Study to Evaluate the Safety and Efficacy of rAd-IFN/Syn3 Following Intravesical Administration in Subjects With High Grade, BCG Refractory or Relapsed Superficial Bladder Cancer

Status: 
Completed
Sponsor: 
FKD Therapies Oy
Enrollment: 
40
Study Design: 
This was a Phase II multicenter study targeting BCG unresponsive high grade NMIBC patients and refused to undergo radical cystectomy were randomized to one of two different Instiladrin viral particle dosages for their disease. The patients received treatments every 3 months for a total of 4 treatments if they continued to respond to therapy without a recurrence.
Rationale: 
Instiladrin is a non-replicating recombinant adenovirus vector containing the human interferon alpha-2b gene. It is administered intravesically and serves as a gene transfer vector and is formulated with Syn3, a polyamide surfactant that enhances the adenoviral transduction of the bladder lining. This allows for more reliable viral transduction of the IFNα-2b gene and ultimately production of IFNα-2b in the bladder. IFNα-2b is believed to be a key early cytokine in the immune response initiated by BCG and Instiladrin allows for more reliable production of this cytokine.
Endpoints: 
The primary endpoint was freedom from high grade recurrence-free survival (RFS) at 12 months defined by negative bladder biopsies.
Comments: 
This trial is limited for many reasons including the small number of patients and the lack of a comparison control group given the heterogeneity of this disease and the multiple pathologic cohorts. Interestingly, the RFS was least in the pure CIS patients at 12 months which is unfortunate since CIS that no longer responds to BCG some is among the most difficult to treat.. Furthermore, without a comparison control group, it is unknown if the high RFS seen at 12 months in Ta or T1 disease was due to the Instiladrin or to the resection of disease. However, it was tolerable and the phase III trial has already been completed and so results are eagerly anticipated.
Results: 
The disease states of the 40 patients consisted of 21 pure CIS, 4 CIS + Ta, 5 CIS + T1, 4 Ta, and 6 T1. Overall, the 12-month high grade RFS was 35% and was comparable between the two groups that only differed in the number of viral particles received. RFS at 12 months was highest in Ta or T1 patients at 50% and lowest in pure CIS patients at 29%. On long-term follow-up, seven patients who recurred with disease on the trial died within a median of 16 months. Although none of the deaths was thought to be treatment-related, at least two of the deaths were due to disease progression. The most common treated-related adverse events (AEs) were urgency (40%), dysuria (40%), and fatigue (33%). However, none of the patients experienced grade 4-5 AEs.

An Open Label, Single Arm, Phase II, Multicenter Study of the Safety and Efficacy of CG0070 Oncolytic Vector Regimen in Patients With Non-Muscle Invasive Bladder Carcinoma Who Have Failed BCG Therapy and Refused Cystectomy

Status: 
Open
Sponsor: 
Cold Genesys, Inc
Enrollment: 
66
Study Design: 
The Phase II single-arm multicenter trial targeted BCG unresponsive high-grade NMIBC patients who refused radical cystectomy. In the reported trial, interim results were published in 45 patients treated on the trial with at least 6 months of follow-up.
Rationale: 
CG0070 is a replication-competent oncolytic adenovirus that selectively replicates in retinoblastoma (Rb) pathway-defective cells that are often present in bladder cancer. The adenovirus also contains a transgene for granulocyte-macrophage colony-stimulating factor (GM-CSF), a cytokine that can active the immune system. CG0070 works by 2 major mechanisms: 1) induction of tumor lysis by selective replication in Rb-deficient tumor cells and 2) local GM-CSF production that augments immunogenic cell death.
Endpoints: 
The primary endpoint was 6-month complete response (CR) rate defined by absence of disease on cystoscopy, cytology, and random biopsies.
Comments: 
This trial is limited for many reasons including small numbers of patients, an interim analysis, and no comparison a control group given the heterogeneity of this disease and the multiple pathologic cohorts. Nevertheless, important takeaways from this interim analysis are that 1) CIS tumor respond best to this therapy and 2) pure T1 patients should be followed closely and counseled extensively on the need for early cystectomy. Finally, with an explosion of clinical trials in BCG unresponsive high grade NMIBC, it is important to remember that there is a real, albeit low risk of progression to muscle invasion.
Results: 
The disease characteristics of the 45 patients consisted of 24 pure CIS, 8 CIS + Ta, 4 CIS + T1, 6 Ta, and 3 T1. The overall 6-month complete response (CR) rate was 47% for all patients. CR was highest in pure CIS patients at 58% and lowest in pure Ta/T1 patients at 33%. Of note, none of the 3 pure T1 patients had a CR at 6 months and one patient (with Ta and T1 disease) progressed to muscle invasion. The most common treatment-related adverse events (AEs) were bladder spasms (36%), hematuria (28%), and dysuria (25%). However, none of the patients experienced grade 4-5 AEs.

Keynote 57: A Phase II Clinical Trial to Study the Efficacy and Safety of Pembrolizumab (MK-3475) in Subjects With High Risk Non-muscle Invasive Bladder Cancer (NMIBC) Unresponsive to Bacillus Calmette-Guerin (BCG) Therapy

Status: 
Recruiting
Sponsor: 
Merck Sharp & Dohme Corp
Enrollment: 
260
Study Design: 
Eligible patients had high-risk NMIBC unresponsive to BCG who refuse or are ineligible for cystectomy. Patients with papillary disease were fully resected prior to therapy. There were two cohorts: A) carcinoma in situ (CIS) with or without high grade papillary disease and B) high grade papillary disease without CIS. Subjects received pembrolizumab every 3 weeks and had standard cystoscopy, cytology, and if indicated, biopsy every 12 weeks for 2 years followed by every 24 weeks for 2 years.
Rationale: 
High-risk (HR) non-muscle invasive bladder cancer (NMIBC) is defined as carcinoma in situ (CIS), T1 tumor and/or high grade Ta tumor. The CR rate from TURBT and intravesical BCG is approximately 70%, however, a significant percentage of patients with high risk disease experience a recurrence and progression risk is 30-40% over a 10-year period. This is a single arm open-label Phase II study of pembrolizumab (MK-3475) 200mg IV every 3 weeks in patients unresponsive to BCG who refuse or are ineligible for cystectomy. Due to some of the remarkable long lasting responses and rapid approval of PD-1/PD-L1 inhibitors in metastatic urothelial cancer, several trials are ongoing to evaluate the impact of these drugs in patients with BCG unresponsive high risk NMIBC. In the absence of novel therapy, these patients ultimately are treated with radical cystectomy which is a potentially morbid operation. Therefore, this trial is the first of many that are ongoing to look at the potential impact of checkpoint inhibitors in localized high-risk urothelial cancer.
Endpoints: 
Primary Endpoints: In Cohort A, complete response (defined as the absence of high risk NMIBC) up to 3 years is the primary endpoint. In Cohort B, disease-free survival up to 3 years is the primary endpoint. Secondary Endpoints: The duration of response in Cohort A (absence of any disease either high-risk or low-risk NMIBC) along with overall safety/tolerability.
Comments: 
In this trial there was a very low risk of “missing the window of opportunity” for radical cystectomy as no patients progressed to muscle invasive disease and the complications of radical cystectomy were not increased. Although this preliminary data is exciting and establishes safety and efficacy, it may fall short of the bar set by expert consensus suggesting that novel therapies with activity in CIS BCG unresponsive NMIBC should result in an initial 40-50% CR rate at 6 months with a more durable CR of 30% at 12 months. Furthermore, this finding raises several important questions in patients who achieve a CR such as how long should therapy be continued and can the cost be justified especially if treatment continues beyond 12 months? This interim analysis is of interest, but 12-month data are needed.
Results: 
At ESMO 2018, Dr. De Wit and colleagues presented a 38.8% complete response (CR) rate in 40/103 patients in Cohort A (CIS containing BCG unresponsive high risk NMIBC) at 3 months among 103 patients. The median time to CR was 12.4 weeks and 80% had a CR duration of greater than or equal to 6 months. However, 25% of patients experienced recurrent NMIBC after CR. No patient developed muscle-invasive or metastatic bladder cancer.

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