The Current Landscape of Neoadjuvant Single Agent Therapy in Patients with Cisplatin Ineligible Clinically Localized, Muscle Invasive Bladder Cancer


Bladder cancer is currently the 10th most commonly diagnosed malignancy worldwide. It is estimated that approximately 110,500 men and 70,000 women are annually diagnosed with bladder cancer globally.1 While the majority of patients are diagnosed with non-muscle invasive disease (i.e. carcinoma in situ, Ta, and T1), approximately 25 to 33% of patients are initially diagnosed with muscle invasive bladder cancer and a meaningful proportion of patients initially diagnosed with non-muscle invasive disease will subsequently progress to MIBC.1

Radical cystectomy and trimodal therapy (i.e. maximal TURBT, chemotherapy, and radiotherapy) remain standard of care options for treatment of patients with clinically localized, muscle invasive disease.2,3 However, survival outcomes in this cohort of patients remain limited with five-year survival rates of 70% in patients with bladder-confined disease and 38% in those with extravesical extension and/or lymph node involvement.4

While neoadjuvant cisplatin-based chemotherapy combinations have demonstrated five-year overall survival benefits of at least 5%,5 a significant proportion of patients remain “cisplatin ineligible”, defined by at least one of the following criteria:6

  1. Performance status two or worse
  2. Glomerular filtration rate <60 ml/min
  3. Grade >2 audiometric loss
  4. Peripheral neuropathy
  5. New York Heart Association class III heart failure

While current guidelines still recommend proceeding directly to radical cystectomy in patients who are cisplatin-ineligible,3 immunotherapeutic agents, that have demonstrated efficacy in patients with metastatic bladder cancer,7 and enfortumab vedotin, an anti-Nectin 4 antibody-drug conjugate, are increasingly being evaluated in the neoadjuvant setting with promising results. In this Center of Excellence article, we review the latest evidence for single agent immunotherapy and enfortumab vedotin in the neoadjuvant setting prior to radical cystectomy in patients with cisplatin ineligible, clinically localized, muscle invasive bladder cancer.

PURE-01: Pembrolizumab

The PURE-01 study is an open-label, single-arm, phase II trial that evaluated three cycles of neoadjuvant pembrolizumab 200 mg given every three weeks prior to radical cystectomy in patients with clinical stage T2-3bN0M0 urothelial carcinoma predominant bladder cancer. Patients were included irrespective of cisplatin eligibility. Results of the primary endpoint, the proportion of patients achieving an ypT0N0 disease state in the intention-to-treat population, were initially reported in 2018.8 Of the fifty patients enrolled between February 2017 and March 2018, 21 (42%) achieved ypT0 disease state and 27 (54%) were downstaged to <ypT2. Biomarker analysis of programmed death-ligand 1 (PD-L1) expression using the combined positive score (CPS) demonstrated that ypT0 was achieved in 54.3% of patients with PD-L1 CPS ≥ 10%, compared to 13.3% in those with CPS <10%. A significant nonlinear association between tumor mutation burden (TMB) and ypT0 was observed, with a cutoff at 15 mutations/Mb.

An updated report of survival outcomes in an expanded sample size of 155 patients with a median follow-up of 39 months (IQR: 30 – 47 months) was subsequently published in 2022. This updated analysis demonstrated that 57 patients (39.8%) achieved a ypT0N0 response, with 83 patients (53.5%) achieving pathologic downstaging to <ypT2N0.9

Overall, the three-year event-free and overall survival were 74.5% (95% CI: 67.8 to 81.7%) and 83.8% (95% CI: 77.8 to 90.2%), respectively. Within the subgroup of patients who did not receive chemotherapy (N = 125), three-year recurrence free survival was:

  1. ypT0N0: 96.3% (95% CI: 91.6 – 100%)
  2. ypT1/a/isN0: 96.1% (89 – 100%)
  3. ypT2-4N0: 74.9% (60.2 – 93.0%)
  4. ypTanyN1-3: 58.3% (36.2 – 94.1%)


On multivariable analysis, patients with higher CPS had lower rates of events (HR: 0.97, 95% CI: 0.95 to 0.99, p=0.003). Three-year event-free survival was 59.7% (95% CI: 47.5 to 75.1%), 76.7% (95% CI: 66.0 to 89.2%), and 89.8% (95% CI: 81.7 to 98.6) in patients with low (N = 51), intermediate (N = 52), and high (N = 49) PD-L1 CPS, respectively (p = 0.001).


With regards to the safety profile, a total of 12 patients (7.7%) did not receive radical cystectomy because of systemic progression or patient refusal. A total of 47 patients (30.3%) developed treatment-related adverse events, with grade 3–4 events observed in seven patients (4.5%). None of the patients experienced radical cystectomy-preventing treatment-related adverse events.9 

ABACUS Trial: Atezolizumab

The ABACUS trial is a single-arm phase II trial that investigated neoadjuvant use of atezolizumab prior to radical cystectomy in cisplatin ineligible/refusing patients with muscle invasive bladder cancer, with a primary endpoint of pathologic complete response. Between May 2016 and June 2018, 95 patients were recruited of whom 88 patients were assessable for the primary endpoint (87 patients had cystectomy). Eight patients did not undergo a cystectomy, three of which were treatment related. The median time from starting atezolizumab to surgery was 5.6 weeks (IQR: 4 to 6.9 weeks). The study met its primary outcome of pathologic complete response with a rate of 31% (95% CI: 21 to 41%). One-year relapse-free survival was 79% (95% CI: 67–87%). Pathologic complete response rates and probability of survival stratified by PD-L1-/PD-L1+ and >/<= median CD8 count are as follows:

Radiological responses (RECIST v.1.1) and progression before surgery occurred in 22% (95% CI: 13 to 35%) and 16% (95% CI: 7 to 27%) of cases, respectively. A total of 17% of patients had grade 3-4 surgical complications, most common of which was wound dehiscence (6%). One patient had surgical complications resulting in postoperative death. Grade 3 or 4 adverse events occurred in 10 of 95 (11%) patients. Adverse events that prevented cystectomy (n = 3) included deterioration of performance status, myocardial infarction and pneumonia.10

AURA (Oncodistinct-004) Cohort 2: Avelumab

The AURA trial is a prospective, multicenter, randomized, phase II trial for patients with cT2-4aN0-2M0 bladder carcinoma, with accrual and treatment stratified by eligibility for cisplatin chemotherapy. Cohort 1 included cisplatin eligible patients who were randomized to either Gem-Cis + Avelumab versus dd-MVAC + avelumab. Cohort 2 included cisplatin ineligible patients randomized in a 1:1 fashion to either four cycles of paclitaxel-gemcitabine (PG) plus avelumab every 2 weeks or 4 cycles of avelumab every 2 weeks.


The authors included 56 cisplatin-ineligible patients who were evaluable, 28 of whom were randomized to PG + avelumab and 28 of whom were randomized to avelumab alone. The primary study endpoint was pathological complete response, with secondary endpoints of pathologic downstaging rate (< ypT2N0) and safety. A pathologic complete response was achieved in 36% of patients in the avelumab alone arm versus 18% of patients in the combined PG + avelumab arm. Downstaging to < ypT2N0 was achieved in 39% of patients in the avelumab alone arm versus 21% of patients in the combined PG + avelumab arm. Five patients did not receive the planned four cycles of treatment: three patients in the PG + avelumab arm experienced toxicity which precluded completing the schedule therapy and two patients in the avelumab arm ceased treatment early due to patient/physician decision. The median time from treatment initiation to surgery was 82 days (55-144) for those receiving PG + avelumab and 67 days (38-89) for those receiving avelumab alone.


Two patients in the PG + avelumab arm experienced grade 3 immune related-adverse events (hepatitis and pneumonitis), which resulted in avelumab discontinuation for 1 patient, compared to none in the avelumab alone arm. No treatment-related deaths were reported. The most common immune-related AEs of any grade were asthenia (15%), skin toxicity and myalgia/arthralgia (each 5%). 

PrE0807: Nivolumab

PrE0807 is a phase Ib multi-institutional trial of patients with localized muscle-invasive bladder cancer treated with two neoadjuvant doses (4 weeks apart) of nivolumab 480mg (anti-PD-1) alone in cohort 1 or nivolumab 480 mg + lirilumab 240 mg (antibody against killer immunoglobulin-like receptor antibody KIR2D) in cohort 2 prior to radical cystectomy without adjuvant therapy. Cohorts were enrolled sequentially and were not randomized. Key eligibility criteria included stage cT2-4aN0-1M0, ≥20% tumor content at TURBT, and cisplatin-ineligibility (Galsky criteria) or refusal. The primary endpoint was safety manifested as the rate of grade 3 or greater treatment-related adverse events assessed in each cohort with CTCAE v5.0. Key secondary endpoints included the percentage of patients who had radical cystectomy > 6 weeks after last neoadjuvant dose due to treatment-related adverse events, ypT0N0 and < ypT2N0 rates. The trial design for PrE0907 was as follows:


In cohorts 1 and 2, 13 and 29 patients, respectively, completed the intended neoadjuvant treatment, and 41/43 underwent radical cystectomy (12/13 cohort 1, 29/30 cohort 2). One patient progressed to metastatic disease prior to radical cystectomy (cohort 1), and one withdrew consent prior to being treated (cohort 2). The median time from the last neoadjuvant dose to radical cystectomy was 27 (95% CI 24-29) days. There was no radical cystectomy delayed more than 6 weeks from treatment completion due to treatment-related adverse events. Grade 3 treatment-related adverse events occurred in 0% with nivolumab and 6.7% (90%: CI: 1.2 to 19.5%) in nivolumab + lirilumab (1: arthralgia, 1: gout, 2: hip pain) that all resolved, and there were no Grade 4/5 treatment-related adverse events occurred.

Of 40 patients with muscle-invasive bladder cancer who underwent radical cystectomy, ypT0N0 rates for nivolumab and nivolumab + lirilumab were 8% and 18%, while < ypT2N0 rates were 17% and 29%, respectively.

EV-103 Cohort H: Enfortumab Vedotin

Enfortumab vedotin is an antibody-drug conjugate directed to Nectin-4, which is highly expressed in urothelial cancer, and has been shown to benefit locally advanced or metastatic urothelial cancer patients in Phase II and III trials,12,13 including cisplatin ineligible patients. 

Cohort H of the EV-103 phase 1b/2 trial (NCT03288545) enrolled cisplatin ineligible patients with cT2-T4aN0M0 muscle-invasive bladder cancer who were eligible for radical cystectomy and pelvic lymph node dissection and had an ECOG of 0-2. Patients received three cycles of neoadjuvant enfortumab vedotin (1.25 mg/kg) on Days 1 and 8 of every 3-week cycle prior to radical cystectomy and pelvic lymph node dissection. The primary endpoint of the study was pathological complete response rate (ypT0N0) by central review. Key secondary endpoints included pathological downstaging rate (yp T0,Tis,Ta,T1,N0) and safety. The trial design for EV-103 cohort H is as follows:


There were 22 patients treated, with the following clinical stages: cT2 (68.2%), cT3 (27.3%), and cT4 (4.5%) tumors. Among these patients, 68.2% patients had predominant urothelial cancer and 31.8% had a mixed histology. The most common reasons for cisplatin ineligibility included creatinine clearance <60 mL/min (50%) and Grade ≥2 hearing loss (40.9%). There were 19 patients that completed all three cycles of enfortumab vedotin and 21 underwent radical cystectomy and pelvic lymph node dissection, with one patient having a partial cystectomy. The median time from the end of neoadjuvant enfortumab vedotin to cystectomy was 1.8 months (range: 1.0-2.7). Overall, 36.4% (95% CI 17.2-59.3) of patients had a pathological complete response, and pathological downstaging was seen in 50.0% (95% CI 28.2-71.8) of patients. The most common enfortumab vedotin treatment-related adverse events were fatigue (45.5%), alopecia (36.4%), and dysgeusia (36.4%). There were 18.2% of patients that had Grade ≥3 enfortumab vedotin treatment-related adverse events. No surgeries were delayed due to enfortumab vedotin administration.

As follows is a table summarizing outcomes of the single agent immunotherapy trials, highlighting ypT0N0 and <ypT2N0 rates:



Trials of neoadjuvant single agent immunotherapy prior to radical cystectomy have demonstrated promising pathologic responses comparable to those seen with contemporary cisplatin-based multi-agent chemotherapy regimens.11 While long-term survival outcomes are still lacking for these agents in this setting, these promising pathologic responses suggest that immunotherapy agents may become part of the neoadjuvant treatment paradigm, particularly for cisplatin-ineligible patients. In the meantime, while these data mature, upfront cystectomy remains the guideline recommended treatment approach for patients with MIBC who are ineligible for cisplatin-based chemotherapy.

Published: March 2023

Written by: Rashid K. Sayyid, MD, MSc, and Zachary Klaassen, MD, MSc
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