EAU 2019: PURE-02: Phase 2 Study of Neoadjuvant Pembrolizumab, Preceding Radical Nephroureterectomy, for Patients with Localized High-Risk Urothelial Carcinoma of the Upper Urinary Tract

Barcelona, Spain (UroToday.com) Upper tract urothelial carcinoma (UTUC) is a rare condition, making large clinical trials difficult to accrue for. More importantly, known concerns with the accuracy of pre-operative staging, and therefore, difficulties in accurately identifying high-risk patients make clinical trial accrual and accuracy difficult. As such, much of the data for UTUC is often extrapolated from the bladder cancer urothelial carcinoma literature.

While neoadjuvant chemotherapy is the standard of care for bladder cancer, neoadjuvant chemotherapy trials in the management of UTUC with radical nephroureterectomy (RNU) have not yielded comparable results. More recent data from the POUT study (Birtle et al. ASCO GU 2018) is the latest and strongest evidence of the benefit of perioperative (albeit adjuvant) systemic therapy for these high risk patients.

In the bladder cancer world, a recent study by Necchi et al. (J. Clin Oncol 2018) demonstrated that neoadjuvant pembrolizumab had significant antitumor activity in muscle-invasive urothelial bladder carcinoma (PURE-01 study) – even in preliminary analysis with rates comparable to neoadjuvant chemotherapy. This is the first data to support the role of immune checkpoint inhibitors in this disease space.

As certain findings, such as the association with Lynch syndrome and microsatellite instability-high (MSI-H) features in UTUC would favor the use of ICI in early-stage UTUC, the authors extrapolated the PURE-01 results into a new clinical trial focused on UTUC. In the PURE-02 study (NCT02736266), they hypothesize that Pembro, given neoadjuvantly before RNU, could provide significant pathologic downstaging.

Study Design:
This is a multicenter European study single-arm prospective study.

200 mg Pembrolizumab will be administered for 3 courses, every 3 weeks, prior to planned RNU. RNU will be planned at the time of study inclusion to be done within 3 week of the last dose of pembrolizumab. Total window time from diagnosis to RNU will be 12 weeks.

The protocol flow is shown below:

EAU 2019_PURE-02.png

Post-RNU, patients will be managed per guidelines.

Inclusion/Exclusion Criteria:
Eligible patients include those with clinical stage cT1-4 N0M0 UTUC. They must have high-risk features per modified EAU guidelines, defined by the presence of either: high-grade disease (urinary cytology + thickening of renal pelvis/ureteral wall), multifocal disease, tumor greater than 1 cm and high-grade disease as documented by tumor biopsy or urinary cytology, and /or hydronephrosis.

The primary endpoint will be to evaluate the proportion of patients who will achieve a pathologic complete response (pT0). pT0 rates will be considered promising if achieved in at least 6 patients (15%).
Secondary endpoints will include safety, relapse-free survival (RFS), and overall survival (OS).

There will be a correlation to PDL-1 status, assessed with CPS score in the tumor specimens before and after treatment. Further correlative research on tissue/blood samples will include immune-cell profiling, cytokine assessment, gene expression analyses and hybrid capture-based comprehensive genomic profiling, including MSI (determined on 114 loci) and tumor mutational burden (TMB) assessment (on 1.1 Mb of sequenced DNA) (FoundationOne).

Sample Size Expectations and Current Study status: The expected sample size of 40 pts

Presented by: Andrea Necchi, MD, Istituto Nazionale dei Tumori, Milan, Italy

Written by: Thenappan Chandrasekar, MD (Clinical Instructor, Thomas Jefferson University) (twitter: @tchandra_uromd, @JEFFUrology) at the 34th European Association of Urology (EAU 2019) #EAU19 conference in Barcelona, Spain, March 15-19, 2019.