EAU 2021: PURE-02: An Open-Label, Single-Arm, Feasibility Study of Neoadjuvant Pembrolizumab Before Radical Nephroureterectomy (Rnu) in Patients With High-Risk, Upper-Tract Urothelial Carcinoma (UTUC)

(UroToday.com) In this abstract at the 2021 European Association of Urology (EAU) annual meeting, Dr. Andrea Necchi presents the preliminary, feasibility results of the PURE-02 study, which assesses the use of pembrolizumab before radical nephroureterectomy in patients with high-risk Upper tract urothelial cancer (UTUC).

The PURE-01 study1 tested the activity of preoperative pembrolizumab (pembro) in patients (pts) with muscle-invasive bladder (MIBC), resulting in 38.5% pathologic complete responses (pT0N0). As a result of this study, pembrolizumab is often considered in patients who are cisplatin-ineligible with MIBC.

In the PURE-02 study, the authors aimed to explore the activity of preoperative pembro in a cohort of pts with UTUC. At present, no data had been reported with the use of the immune checkpoint inhibitors (ICI) in localized UTUC.

The primary aim of the PURE-02 cohort was to assess the feasibility of neoadjuvant pembro before radical nephroureterectomy (RNU). A pre-determined sample size of 10 pts who would receive 200 mg pembro, intravenously (IV), every 3 weeks, preceding RNU (planned within 14 days of the last pembro dose). The study included pts with clinical-stage N0M0 UTUC, with high-risk features according to modified EAU guidelines, defined by the presence of either: high-grade disease (urinary cytology and/or biopsy), multifocal disease, ≥2cm tumor mass, hydronephrosis.
- Patients with previous/concomitant bladder urothelial or variant histology were excluded.

The primary endpoints were to prospectively test the reliability of the EAU high-risk UTUC criteria within a prospective study, to assess the clinical activity (number of ypT0N0 responses) and the surgical and medical safety (CTCAE version 4.03). Hybrid capture-based genomic profiling tests were done on tissue and blood samples, and multiparametric magnetic resonance imaging (mpMRI) tests of the renal pelvis and ureter were also investigated.

Jumping to the results, between 05/2018 and 10/2020, they enrolled 10 pts evaluable for the study endpoints: 33% were female, 2 had a renal pelvis, 6 had a ureteral tumor, and 2 both of them.
- Tumor biopsy was not performed in 7 pts (70%) due to the presence of positive cytology and tumor mass (N=4) or multifocal disease (N=3).

Of the 10 patients, 9 patients (90%) completed the pembro administrations, and 1 patient died due to the development of severe myasthenia gravis, myocarditis, myositis, and hepatitis after the 1st pembro course. The remaining patients did not show any grade 2-4 AE.

In terms of oncologic outcomes, two pts (20%) achieved a radiological partial response, 2 received subsequent therapy due to nonresponse (stable disease).
In total, 7 patients underwent RNU: one (14.3%) achieved a ypT1N0 response; the remaining pts were nonresponders.

With regards to biomarkers, 3/6 baseline ctDNA assays were test failures due to the small amount of DNA. mpMRI findings did not help to discriminate a response besides dimensional changes.

Unfortunately, based on the above results, due to the multiple limitations, the authors are concerned about the need and safety of administering single-agent pembro preoperatively in high-risk UTUC. On the other hand, the activity of single-agent therapy is minimal.



Presented by: Andrea Necchi, MD, Head of Genitourinary Medical Oncology at Vita-Salute San Raffaele University and IRCCS San Raffaele Hospital, Milan, Italy

Written by: Thenappan (Thenu) Chandrasekar, MD – Urologic Oncologist, Assistant Professor of Urology, Sidney Kimmel Cancer Center, Thomas Jefferson University, @tchandra_uromd on Twitter during the 2021 European Association of Urology, EAU 2021- Virtual Meeting, July 8-12, 2021.


References:
1. Necchi A, Anichini A, Raggi D, et al. Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study. J Clin Oncol. 2018 Dec 1;36(34):3353-3360. doi: 10.1200/JCO.18.01148. Epub 2018 Oct 20. PMID: 30343614.