CUA 2018: Checkpoint Inhibitors Across the Disease Spectrum: Non-Metastatic Urothelial Carcinoma

Halifax, Nova Scotia (UroToday.com) Dr. Wes Kassouf from Montreal provided an update on the immunotherapy trials that have recently reported for non-metastatic urothelial carcinoma at CUOG multidisciplinary session at CUA 2018. Among patients with MIBC, several small studies have evaluated PD-L1 expression before and after neoadjuvant chemotherapy, noting that PD-L1 expression increases after treatment.



Impressively, 1/3 of patients stained positive for PD-L1 after neoadjuvant chemotherapy, however there is conflicting data regarding PD-L1 expression and clinical outcomes following neoadjuvant chemotherapy. Furthermore, higher CTLA-4 gene expression appears to be associated with more aggressive disease, however the impact on survival outcomes is inconclusive. There are several adjuvant immunotherapy trials currently underway for patients following cystectomy including: 
  • AMBASSADOR: pembrolizumab vs observation. Co-primary endpoint DFS and OS 
  • CheckMate 274: nivolumab vs observation. Endpoint DFS (all patients and for PD-L1 +) 
  • IMvigor 010: atezolizumab vs observation. Endpoint DFS 
There are currently 10 phase I/II neoadjuvant trials (single arm IO alone, IO+IO, IO + chemotherapy) ongoing, of which Dr. Kassouf concluded his talk by going in depth to describe two of these trials which have very recently reported initial results last month at ASCO 2018.  

The PURE-01 trial is an open-label, single-arm, phase 2 study evaluating pembrolizumab prior to radical cystectomy [1]. Key inclusion criteria for this trial included patients with: (i) predominantly urothelial carcinoma histology (>50%), (ii) clinical stage ≤3bN0M0 disease by CT, MRI or PET/CT within four weeks of randomization, (iii) residual disease after TURBT, (iv) GFR ≥20 ml/min, and (v) ECOG performance status 0-1. The primary outcome was pathologic complete response (pT0) at the time of radical cystectomy in the intention to treat (ITT) population. The study started enrolling patients in February 2017, and at a data cutoff of May 10, 2018 the median follow-up for PURE-01 was 8 months. The first stage of enrollment included 43 patients, including 35 males/7 females, with 37.2% of patients with cT2N0 disease, 58.1% with cT3N0, and 4.7% of patients with T2-3N1. At the time of this analysis, there were 17/43 patients that were pT0 (39.5%, 95%CI: 26.3-54.4) and 5 <pT2 (total <pT2 rate: 51.2%). Treatment failures were categorized as (i) ypT2-4 ypN0: n=7, 16.3%; (ii) ypTany ypN+: n=9, 20.9%; (iii) clinical failure (additional neoadjuvant chemotherapy): n=5, 11.6%.  

The ABACUS trial is a single arm, phase II study investigating two cycles of atezolizumab (1200mg every three weeks) prior to radical cystectomy among patients with T2-4N0M0 urothelial carcinoma [2]. Other key eligibility criteria included residual disease post-TURBT and not fit for/rejected cisplatin based chemotherapy. The main primary endpoint was pathological complete response occurring in ≥20% of patients. There were 74 patients that received atezolizumab (n=59 received two cycles; n=15 received one cycle). Among these patients, 67 underwent subsequent radical cystectomy. Among the seven patients not receiving surgery was one patient with disease progression (treated with chemotherapy) who was included in the analysis of the primary efficacy endpoint (n=68). The median age of the 68 patients was 71 years (range 53-85), and the baseline pT2 rate was 71%, pT3 was 22%, and pT4 was 7%. The pathologic complete response rates were as follows: 

  • All patients: 20/68 (29%) – pT0, n=16; pTis, n=4 
  • PD-L1 positive patients: 10/25 (40%) 
  • PD-L1 negative patients: 5/31 (16%) 
  • cT2 patients: 17/48 (35%) 
  • cT3-T4 patients: 3/20 (15%) 
Although the metastatic first- and second-line setting clinical trials are ahead of the non-metastatic trials, Dr. Kassouf notes that based on the plethora of ongoing phase I/II trials, with phase III trials likely to follow, the next decade of immunotherapy in localized bladder cancer will be exciting. 

Presented By: Wassim Kassouf, McGill University Medical Center, Montreal, Quebec, Canada 

Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre Twitter: @zklaassen_md at the 73rd Canadian Urological Association Annual Meeting - June 23 - 26, 2018 - Halifax, Nova Scotia

References: 
1. Necchi A, Briganti A, Bianchi M, et al. Preoperative pembrolizumab before radical cystectomy for muscle-invasive urothelial bladder carcinoma: Interim clinical and biomarker findings from the phase 2 PURE-01 study. ASCO 2018 abstr 4507. 
2. Powles T, Rodriguez-Vida A, Duran I, et al. A phase II study investigating the safety and efficacy of neoadjuvant atezolizumab in muscle invasive bladder cancer (ABACUS). ASCO 2018 abstr 4506.
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