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

NIMBUS Trial

Status: 
Completed
Sponsor: 
European Association of Urology Research Foundation
Enrollment: 
345
Study Design: 
BCG naïve patients with high grade Ta or T1, primary or recurrent, single or multiple papillary urothelial cancer with or without CIS after adequate resection of papillary component (with muscle present in the specimen) were randomized to standard BCG frequency (SF) or reduced BCG frequency (RF). The SF arm consisted of 15 total instillations: a) induction course of weekly BCG for 6 weeks followed by b) maintenance courses of weekly BCG for 3 weeks at month 3, 6, and 12. The RF arm consisted of 9 total instillations: a) induction course of BCG at week 1, 2, and 6 followed by b) maintenance courses of BCG at only weeks 1 and 3 at month 3, 6, and 12. Cystoscopy and cytology were performed every 3 months for the fi rst two years and every six months afterwards. Patients completed study at first recurrence or after occurrence of new CIS, upper tract urothelial carcinoma, prostatic urethral disease, distant metastases, or requiring systemic chemotherapy. The study was designed to establish therapeutic equivalence defined as the lower part of the confidence interval (CI) (using one-sided 2.5% level of significance) being higher than a hazard ratio of 0.75 for recurrence. The sample size was calculated to be 412 per arm after recruitment delay due to BCG shortage led to re-defi nition of statistical assumptions.
Rationale: 
BCG is the standard treatment for high risk non-muscle invasive bladder cancer (NMIBC) and given recent data suggesting comparable efficacy and improved tolerability with reduced dosing as well as recent challenges in administration given BCG shortages, this trial evaluated whether a reduced number of standard dose BCG instillations were non-inferior to the standard number and dose of BCG instillations for patients with high grade NMIBC.
Endpoints: 
The primary endpoint was time to first recurrence. Secondary endpoints included progression to muscle-invasion, number and grade of recurrent tumors, and side effects.
Comments: 
NIMBUS was designed based on animal data demonstrating profound Th1-mediated cytokine responses at weeks 1 and 6 of induction BCG equivalent to an entire 6-week induction phase. The maintenance course was also shortened in the RF arm based on data from CUETO 98013 demonstrating that one maintenance instillation is sufficient. However, the results in this randomized trial demonstrated an increased recurrence rate in the RF arm. There are obvious limitations to this trial (lack of central pathology review, stopping maintenance at 1 year) but the trial did factor in BCG shortages and 90% of patients had a re-TUR. Despite data in animal models, current SF BCG protocols result in lower recurrence rates and should remain the standard of care. This trial does not address the common practice of maintaining standard frequency BCG administration but with reduced dosing (e.g. one-half to one-third dose) for maintenance instillations.
Results: 
As of November 2021, 359 patients were randomized with 177 to the RF arm and 182 to the SF arm. Majority of tumors were T1 and concomitant CIS seen in 28% of the RF arm and 29% of the SF arm. After fourteen months of median follow-up for all patients, ITT analysis demonstrated disease recurrence in 85 (24%) of the 359 patients: 55 (31%) of the 177 RF patients and 30 (16%) of the 182 SF patients. Univariate Cox regression demonstrated a HR of 0.47 (95% CI: 0.30-0.74) for first recurrence favoring the SF arm. The trial closed early due to inferiority of the RF arm. Interestingly, seven patients progressed to muscle invasive bladder cancer with one in the RF arm and six in the SF arm.

ONCOFID-P-B (PACLITAXEL-HYALURONIC ACID) in the Intravesical Therapy of Patients With Non-muscle Invasive Cancer of the Bladder

Status: 
Completed
Sponsor: 
Fidia Farmaceutici S.p.A.
Enrollment: 
60
Study Design: 
Oncofid-P-B is a novel compound under development by Fidia Farmaceutici S.p.A. with specific binding to the CD44 receptor. This is a single-arm, multicenter European study consisting of weekly intravesical instillation of Oncofid-P-B for 12 weeks (intensive phase) followed by 12 monthly instillations (maintenance phase). Patients with CIS ± Ta-T1, unresponsive or intolerant to BCG, unwilling or unfit for cystectomy were enrolled. Patients were deemed BCG-refractory and were not BCG-unresponsive by current standards. Patients with muscle invasive bladder cancer (MIBC) and/or concomitant cancer of the upper urinary tract were excluded.
Rationale: 
The urothelial membrane resists penetration of chemotherapeutic agents preventing effective therapy of non-muscle invasive bladder cancer (NMIBC). Oncofid-P-B is a novel intravesical agent consisting of paclitaxel conjugated to hyaluronic acid (HA). It is postulated that the HA moiety binds selectively to CD44 which is over-expressed on the surface of urothelial tumors allowing for increased paclitaxel activity. In vitro studies demonstrate greater cytotoxicity in cell lines with Oncofid-P-B compared to paclitaxel alone. A previous Phase I study established good tolerability and efficacy in a BCG-refractory CIS cohort treated with a weekly 6-week course. This study is a Phase II, single-arm trial evaluating the effects of an intensive or induction phase followed by a maintenance phase of treatment with Oncofid-P-B in patients with high risk, BCG unresponsive CIS+/- Ta or T1 disease.
Endpoints: 
The safety and tolerability profile was the primary endpoint. The secondary endpoints were the antitumor activity of Oncofid-P-B measured at the end of the intensive phase and every three months during the maintenance phase, compliance with treatment, and evaluation of systemic absorption of Oncofid-P-B. The complete response rate was defined as a negative cystoscopy, negative biopsy of the urothelium (performed after the intensive phase or whenever a suspicious area was found) and a negative cytology.
Comments: 
This phase II study is promising and demonstrated good safety and tolerability and early efficacy results on par with other investigational agents in the BCG-unresponsive NMIBC clinical space. Of note, seven patients only received a single induction course of BCG followed by additional chemotherapy and were enrolled in order to mitigate the future risk of disease progression and so it is conceivable that the response rates seen are higher than what would be seen in a truly BCG-unresponsive cohort. The initial results warrant further evaluate in Phase II/III studies.
Results: 
Twenty-one patients were enrolled and twenty completed treatment and were evaluable. At study entry, 85% of patients had CIS only and 80% of all patients were unresponsive to BCG whereas 20% of all patients were intolerant to BCG. The compliance rate with the intensive treatment regimen was 91.6%. The complete response rate was 75% at the end of the intensive phase. The complete response rate was 65% at month 3 of maintenance therapy and was 40% at the end of the maintenance phase (15 months after treatment start). Ultimately, twelve patients did not respond and two had disease progression (one with lamina propria invasion and one with muscle invasion). Median time to failure (e.g. persistent CIS, disease relapse or progression) was 14.1 months in all patients. Eighteen (90%) patients experienced AEs and SAEs were only reported in two (10%) patients. One patient experienced death but not related to Oncofid-P-B and felt to be secondary to concomitant disease with squamous lung carcinoma. There was no systemic absorption of the drug.

A Phase II Trial of sEphB4-HSA in Combination With Anti PD1 Antibody Pembrolizumab (MK-7435) for Metastatic Urothelial Cancer Refractory to Platinum

Status: 
Recruiting
Sponsor: 
University of Southern California
Enrollment: 
60
Study Design: 
Patients with platinum-refractory metastatic urothelial cancer and no prior PD-(L)-1 therapy were treated with the combination of sEphB4-HSA and pembrolizumab in a single-arm, single-center Phase II study. Treatment was continued until progression or unacceptable toxicity and response was measured every 6 weeks using RECIST 1.1. Tumor tissue for all evaluable patients was tested for B2 expression by immunohistochemistry.
Rationale: 
EphrinB2 (B2) is expressed in metastatic urothelial cancer and it blocks immune cell traffic into the tumor. B2 can be blocked by EphrinB4 (B4) which can theoretically increase immune cell traffic and sEphB4-HSA is a fusion protein of soluble EphrinB4 and albumin that binds to EphrinB2. This trial evaluates the combination of pembrolizumab in combination with sEphB4-HSA in previously treated metastatic urothelial cancer with the hypothesis that an influx of immune cells would enhance the response to a anti-PD-(L)-1 therapy.
Endpoints: 
The primary endpoint was overall survival (OS) while secondary endpoints were progression free survival (PFS), duration of response (DOR), and objective response rate (ORR).
Comments: 
This trial demonstrated impressive results with combination therapy that was more pronounced in those patients with EphrinB2 expression. The combination has received breakthrough designation by the FDA. Given the mechanism of action, it will be interesting to see whether the fusion protein will be synergistic with other immune therapies such as CTLA-4 inhibitors or possibly even BCG.
Results: 
69 patients were enrolled. The main sites of disease were the nodes, lungs, and the liver. The median overall survival was 14.4 months. The ORR was 38% with a median PFS of 4.0 and a median DOR of 8 months. Expression of B2 was seen in 46 (65.7%) patients. ORR was 57.5% among B2+ patients with a DOR of 27 months. Among the toxicities, hypertension was the most common attributable to B4. Other toxicities include fatigue, nausea, headache, anorexia, proteinuria, hyperuricemia, rash, anemia, and elevated AST. The percentage of grade 3-4 toxicities seen was 42%.

A Phase 1b-2 Study to Evaluate Safety, Efficacy, Pharmacokinetics, and Pharmacodynamics of Various Regimens of Erdafitinib in Subjects With Metastatic or Locally Advanced Urothelial Cancer

Status: 
Recruiting
Sponsor: 
Janssen Research & Development, LLC
Enrollment: 
126
Study Design: 
Patients with metastatic urothelial cancer with select FGFR alterations, measurable disease, no prior systemic therapy, and who were ineligible to receive cisplatin were enrolled. Any PD-(L)-1 status could be enrolled. Patients were randomized to either erdafitinib alone or erdafitinib and cetrelimab.
Rationale: 
Currently, first-line therapy for cisplatin-ineligible patients with metastatic urothelial cancer is alternative chemotherapy or anti-PD-(L)-1 monotherapy. The pan-fibroblast growth factor receptor (FGFR) inhibitor, erdafitinib, is indicated as second-line therapy in metastatic urothelial cancer with targetable FGFR alterations. The phase Ib trial determined a tolerable dose of erdafitinib and the anti-PD-1 antibody, cetrelimab, as a second-line regimen in metastatic patients. The phase II part of the trial is reported here which evaluates erdafitinib alone or erdafitinib and cetrelimab as a first-line regimen in cisplatin-ineligible patients with FGFR alterations.
Endpoints: 
The primary endpoints were overall response rate (ORR) per RECIST 1.1 and safety. Secondary endpoints included disease control rate, time to response, and duration of response.
Comments: 
The results demonstrate activity with the combination of erdafitinib and cetrelimab in first line, cisplatin-ineligible patients with metastatic urothelial cancer with FGFR alterations. These alterations are more frequent in upper tract tumors than in bladder cancer. Although of interest, other very promising regimens for first line, cisplatin-ineligible patients currently exist (such as enfortumab vedotin and pembrolizumab).
Results: 
The reported results of the Norse Trial at ESMO 2021 were as of July 2021. As of that date, 53 patients were randomized but ORR was evaluable in 37 patients. The ORR was 33% in the erdafitinib arm vs. 68% in the combination arm. The complete response rate was 6% vs. 21%, respectively. The median duration of response was not evaluable in the erdafitinib arm and 6.9 months in the combination arm. The safety data included 48 total patients with the side effects being attributable to the ertafinitib including hyperphosphatemia (58% erdafitinib vs. 58% combination), stomatitis (63% vs. 54%, respectively), and diarrhea (50% vs. 42%, respectively).

Randomized Phase III Study of Gemcitabine/Cisplatine (GC) Versus High-dose Intensity Methotrexate, Vinblastine, Doxorubicine and Cisplatin (HD-MVAC) in the Perioperative Setting for Patients With Locally Advanced Transitional Cell Cancer of the Bladder

Status: 
Open
Sponsor: 
University Hospital, Rouen
Enrollment: 
500
Study Design: 
The GETUG/AFU V05 VESPER Phase III Trial randomized trial was conducted at 28 French centers comparing 4 cycles of gemcitabine and cisplatin (GC) to 6 cycles of dose dense or high-dose MVAC in the perioperative treatment of muscle-invasive bladder cancer (MIBC). Treatment was given either in the neoadjuvant or adjuvant window. Patients with pure or mixed urothelial bladder cancer were enrolled but neuroendocrine histology was excluded. All patients were platinum-eligible.
Rationale: 
Gemcitabine and cisplatin are commonly used for perioperative (neoadjuvant or adjuvant) chemotherapy based on data demonstrating similar efficacy with better tolerance as compared to MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) in metastatic disease. In metastatic disease, high-dose (HD)-MVAC has better efficacy and this trial evaluates whether HD-MVAC has better efficacy in the perioperative setting in terms of progression-free survival.
Endpoints: 
The primary endpoint was progression-free survival (PFS) at three years.
Comments: 
The trial demonstrated a better organ-confined rate and a better PFS at 3 years in the HD-MVAC arm. Among the planned cycles in each arm of the trial, fewer patients in the HD-MVAC arm were treated with all planned cycles compared to the GC arm. Despite that, the cystectomy rate was the same in both arms suggesting that if a patient can tolerate this neoadjuvant regimen, it may result in better local control and progression-free survival. This regimen should be considered as a new standard for fit patients with muscle invasive urothelial cancer. The small number of patients treated with adjuvant chemotherapy prevent any conclusions about these regimens given on an adjuvant basis.
Results: 
Overall, 437 patients (88%) received neoadjuvant chemotherapy: 84% of the patients in the GC arm and 60% of the patients in the HD-MVAC arm received all planned cycles. 90% and 91% of the patients underwent surgery respectively and organ-confined disease (<ypT3N0) was more frequently seen in the HD-MVAC arm (77% vs. 63%, p=0.001) respectively. The adjuvant group was smaller (only 54 patients) with 81% of the patients in the GC arm and 40% of the patients in the HD-MVAC arm receiving all planned cycles. Overall, the PFS at three years was better in the HD-MVAC arm (64% vs. 56%, HR = 0.77 (95% CI, 0.57-1.02), p=0.066) in all patients (neoadjuvant and adjuvant) but it was significantly better in the neoadjuvant group (66% vs. 56%, HR = 0.70 (95% CI, 0.51-0.96), p=0.025). OS data are not mature yet and final analysis will be done after a median follow-up of 5 years.

Pembrolizumab (MK3475), Gemcitabine, and Concurrent Hypofractionated Radiation Therapy for Muscle-Invasive Urothelial Cancer of the Bladder

Status: 
Open
Sponsor: 
Merck
Enrollment: 
54
Study Design: 
This is a single arm Phase I/II trial evaluating the safety of the combination of pembrolizumab, gemcitabine, and radiation therapy with an initial safety lead-in cohort of 6 patients. This will be followed by a phase II cohort if toxicity is only seen in 1 or zero patients consisting of 48 patients for efficacy evaluation. The results were presented at ASCO 2021. The chemoradiation consisted of whole bladder radiation therapy (52 Gy in 20 fractions over 4 weeks) with twice weekly gemcitabine at 27 mg/m2 for 4 weeks given concurrent with chemoradiation. Pembrolizumab was given as a single lead-in dose (200 mg). Treatment was followed by maximal TURBT 2- 3 weeks afterwards and pembrolizumab 200 mg intravenously was administered every 3 weeks for a total of 3 doses starting day 1 of radiation therapy.
Rationale: 
Chemoradiation is an established treatment for MIBC and this trial is evaluating whether the addition of immunotherapy, specifically, pembrolizumab can improve upon this response. Furthermore, the trial uses an unique endpoint of intact bladder-free survival which minimizes the impact of urinary symptoms and/or recurrence of NMIBC.
Endpoints: 
The primary endpoint was two-year bladder intact event-free survival (BI-EFS) which is a novel endpoint only measured from the time of treatment initiation to the following events: recurrent/residual MIBC post-chemoradiotherapy, nodal or distant metastatic disease, radical cystectomy, or death due to any cause. Secondary endpoints included safety, complete response rate, overall survival and metastasis-free survival. Complete response rate was defined as the absence of any viable residual cancer.
Comments: 
The initial results are exciting given the complete response rate and high bladder-intact free survival rate, albeit with short follow-up. Of course with further follow-up, these numbers can worsen over time but the regimen appears to be safe and outcomes are initially quite reasonable. Another challenge will lie in knowing the ideal radio-sensitizing chemotherapy agent to use along with the best radiation treatment protocol. To that end, the ongoing randomized clinical trial evaluating the use of pembrolizumab with investigator choice of chemotherapy and radiation therapy (NCT 04241185) is actively accruing and will answer more questions.
Results: 
Updated results were presented at ASCO 2021. Six patients were enrolled into a safety cohort followed by 48 patients enrolled into an efficacy cohort. A total of 42 patients (85%) completed all protocol therapy and were included in the analysis. The majority of patients had T2N0 disease (70%) and 75% refused cystectomy. At 12 weeks post-radiotherapy, complete response in the entire cohort was 59%. At a median follow-up of 14.6 months, bladder-intact free survival was 88% at 12 months in the efficacy cohort. Nine patients (19%) were treated with steroids for immune-related adverse events. One patient died of a grade 4 colonic perforation.

Gemcitabine, Cisplatin, Plus Nivolumab in Patients With Muscle-invasive Bladder Cancer With Selective Bladder Sparing (GU-16-257)

Status: 
Open
Sponsor: 
Icahn School of Medicine at Mount Sinai/Hoosier Cancer Research Network
Enrollment: 
76
Study Design: 
This is a single arm, phase II study in which cisplatin-eligible patients with cT2-T4aN0M0 urothelial cancer are treated with TURBT followed by four cycles of gemcitabine/cisplatin and nivolumab and patients reassessed with clinical imaging, cytology, cystoscopy, and biopsies and if patients achieved a clinical complete response rate, then offered a four-month adjuvant period of nivolumab instead of radical cystectomy. Clinical complete response rate is defined as normal imaging, normal cytology, and no tumor or low grade Ta urothelial cancer on biopsy.
Rationale: 
This trial explores the impact of primary chemo-immunotherapy as a sole-treatment for MIBC without the use of radiotherapy. Therefore, this trial is evaluating the use of systemic therapy for localized disease without the use of definitive local therapy.
Endpoints: 
The primary endpoints are clinical complete response rate (cT0 or cTa) and the ability of clinical complete response to predict pathologic complete response (<pT1) in patients undergoing cystectomy and 2 year metastasis-free survival (MFS) in patients pursuing surveillance. Secondary endpoints include the impact of baseline genomic alterations from TURBT (ERCC2, FANCC, RB1, ATM, and tumor mutation burden) on performance of clinical complete response for predicting MFS.
Comments: 
TURBT alone for MIBC has been shown in some series to show excellent response rates and in this study the rates of clinical complete response are lower than historical TURBT series and certainly lower than in studies with definitive local therapy using chemoradiation or radical cystectomy. Furthermore, genomic alterations known to correlate with response to chemoimmunotherapy may not function as biomarkers as they may not correlate with clinical response in all patients.
Results: 
Overall, 76 patients were enrolled and 64 (84%) completed imaging. Thirty-one (48%) of the 64 patients achieved a complete response and 30 of the 31 patients chose adjuvant immunotherapy instead of radical cystectomy. However, 8 of the 31 patients developed a local recurrence and six of them underwent cystectomy and only one patient had >T2N0 disease. Of note, among the patients without complete response who underwent immediate cystectomy (n=28), 32% had ypTanyN+ disease. Finally, among genomic alterations well described to correlate with response to chemoimmunotherapy, only TMB ? 10 mutations/Mb or mutant ERCC2 were associated with a clinical complete response.

Phase III Randomized Trial of Concurrent Chemoradiotherapy With or Without Atezolizumab in Localized Muscle Invasive Bladder Cancer

Status: 
Open
Sponsor: 
SWOG/NRG (National Cancer Institute), Genentech
Enrollment: 
475
Study Design: 
This is a randomized trial for patients with localized muscle-invasive bladder cancer T2-4N0M0 who have refused or are unfit for radical cystectomy or preferentially choose bladder sparing treatment whereby patients are randomized to radiation therapy (three-dimensional conformal or intensity-modulated) with chemotherapy as per the treating physician with or without atezolizumab. The chemotherapy can consist of either gemcitabine, cisplatin, or fluorouracil and mitomycin. Patients treated in the atezolizumab arm are treated every 3 weeks for up to 6 months.
Rationale: 
Chemoradiation has an established therapeutic role in localized muscle-invasive bladder cancer. This cooperative group trial tests the hypothesis that the addition of immunotherapy, specifically atezolizumab, improves bladder intact event-free survival.
Endpoints: 
The primary outcome is bladder intact event-free survival (BI-EFS) rate from the date of randomization to the first documentation of a BI-EFS event, assessed up to 5 years. This composite endpoint includes the absence of muscle invasive bladder recurrence, regional pelvic soft tissue or nodal recurrence, distant metastases, bladder cancer or toxicity related death or cystectomy. Secondary endpoints include: overall survival at 5 years, disease-specific survival, NMIBC recurrence rate, cystectomy rate, and several immunologic and biologic endpoints.
Comments: 
This is an ongoing trial with a target enrollment of 475 patients. As of July 1,2021 172 patients have been registered with a target enrollment of 10 patients per month. The DSMC considered it safe to continue the trial, though it is surprising that there were more grade 3 or high toxicity events in the immunotherapy arm that were deemed not to be immune-related. This suggests that combination therapy may result in a higher number of toxicities that are a result more of combination treatment as opposed to being related to immunotherapy alone.
Results: 
At GU ASCO 2021, safety data were reported for the first 73 patients enrolled on trial. The atezolizumab arm contained 37 patients while the trimodal therapy arm contained 36 patients. Overall, the immunotherapy arm had 23 grade 3 or higher toxicity rates compared to 11 in the trimodal therapy alone arm. Moreover, none of the toxicities were deemed to be immune-related. The most common toxicity was hematological (anemia, lymphopenia and decreased WBC).

A Study to Evaluate Enfortumab Vedotin Versus (vs) Chemotherapy in Subjects With Previously Treated Locally Advanced or Metastatic Urothelial Cancer (EV-301)

Status: 
Open
Sponsor: 
Astellas Pharma Global Development
Enrollment: 
608
Study Design: 
This was an international open-label, phase 3 trial of enfortumab vedotin, an antibody drug conjugate that targets Nectin-4 and carries a Monomethyl Auristatin E (MMAE) Payload, a microtubule-disrupting agent, as compared to investigator’s chemotherapy of choice in patients with locally advanced or metastatic urothelial carcinoma who had previously received platinum-containing chemotherapy and had disease progression during or after treatment with a PD-1 or PD-L1 inhibitor. Patients were randomly assigned in a 1:1 ratio to receive enfortumab vedotin or docetaxel, paclitaxel, or vinflunine.
Rationale: 
Patients with advanced urothelial carcinoma have poor overall survival when recurring after platinum-containing chemotherapy and programmed cell death protein 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor treatment. More novel therapies are needed.
Endpoints: 
The primary end point was overall survival (OS).
Comments: 
The FDA approved enfortumab vedotin for treatment of patients with locally advanced or metastatic UC previously treated with a PD-(L)1 inhibitor and platinum-containing CT in the (neo)adjuvant, locally advanced, or metastatic setting. A second antibody drug conjugate Sacituzumab Govitecan, that targets Targets Trop-2, with a SN-38 Payload, the active metabolite of irinotecan, was also recently approved for locally advanced or metastatic UC previously treated with a PD-L1 inhibitor and either platinum ineligible or previously treated with platinum-containing CT in the (neo)adjuvant, locally advanced, or metastatic setting.
Results: 
301 patients were assigned to receive enfortumab vedotin and 307 to receive chemotherapy. As of July 15, 2020, a total of 301 deaths had occurred (134 in the enfortumab vedotin group and 167 in the chemotherapy group). At the prespecified interim analysis, the median follow-up was 11.1 months. OS was longer in the enfortumab vedotin group than in the chemotherapy group (median 12.88 vs. 8.97 months; hazard ratio for death, 0.70; 95% confidence interval [CI], 0.56 to 0.89; P = 0.001). Progression-free survival(PFS) was also longer in the enfortumab vedotin group than in the chemotherapy group (median 5.55 vs. 3.71 months; HR for progression or death, 0.62; 95% CI, 0.51 to 0.75; P<0.001). The study was halted by the IDMC at this analysis and it was recommended to the sponsor to allow crossover of patients on chemotherapy at PD to enfortumab vedotin.

An Investigational Immuno-therapy Study of Nivolumab, Compared to Placebo, in Patients With Bladder or Upper Urinary Tract Cancer, Following Surgery to Remove the Cancer (CheckMate 274)

Status: 
Open
Sponsor: 
Bristol-Myers Squibb
Enrollment: 
709
Study Design: 
CheckMate 274 is a phase 3, randomized, double-blind, multicenter study of adjuvant nivolumab versus placebo in patients with high-risk MIUC. Inclusion criteria were: Patients with ypT2-ypT4a or ypN+ MIUC who had neoadjuvant cisplatin-based CT, or pT3-pT4a or pN+ MIUC without prior neoadjuvant cisplatin-based CT, and not eligible for or refused adjuvant cisplatin-based CT; radical surgery performed within the past 120 days and disease-free status within 4 weeks of dosing. Patients were randomized 1:1 to nivolumb IV 240 mg every 2 weeks vs. placebo IV every 2 weeks x 1 year. Stratification factors included: PD-L1 status (<1% vs ≥ 1%) , prior neoadjuvant cisplatin-based chemotherapy and nodal status.
Rationale: 
Radical surgical resection is the standard of care for patients with MIUC. Adjuvant therapy after radical surgery is not currently recommended for patients who have received neoadjuvant therapy... For patients who have not had neoadjuvant cisplatin-based CT, adjuvant cisplatin-based CT may be offered but the level of evidence is low. Nivolumab, a PD-1 immune checkpoint inhibitor, is approved as monotherapy for treatment of platinum-resistant metastatic UC. Until this trial , no immunotherapy has shown efficacy as adjuvant therapy in patients with MIUC at high risk for recurrence after radical surgery.
Endpoints: 
The primary endpoints were disease free survival in the intent to treat (ITT) population and DFS in all randomized patients with tumor PD-L1 ≥ 1%.
Comments: 
Nivolumab is the first systemic immunotherapy to demonstrate a statistically significant and clinically meaningful improvement in outcomes when administered as adjuvant therapy to patients with MIUC. The FDA has granted priority review, although the overall survival data are not yet mature. These results may well support nivolumab monotherapy as a new standard of care in the adjuvant setting for patients with high-risk MIUC after radical surgery, irrespective of PD-L1 status and prior neoadjuvant chemotherapy. The results differ from what was found in the adjuvant atezolizumab trial highlighted below.
Results: 
Adjuvant nivolumab significantly improved DFS in patients with high-risk MIUC after radical surgery, both in the ITT and PD-L1 ≥ 1% populations. In the ITT population, the median DFS with nivolumab was 21.0 (17.1–33.4) months vs 10.9 (8.3–13.9) months, HR, 0.70 (98.31% CI, 0.54–0.89) in patients treated with placebo (p < 0.001). In the PD-L1 ≥ 1% population, median DFS was NR (22.0–NE) vs 10.8 (5.7–21.2) months, HR, 0.53 (98.87% CI, 0.34–0.84), respectively (p < 0.001). No deterioration in health related quality of life, as measured by change in EORTC QLQ-C30 global health status score, was observed with nivolumab vs placebo.

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