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Authors: Trevisani Francesco , DI MARCO FEDERICO , Necchi Andrea , Raggi Daniele , Bettiga Arianna , Vago Riccardo , Capitanio Umberto , Gallina Andrea , Colombo Renzo , Salonia Andrea , Briganti Alberto , Montorsi Francesco 
Published: June 2020

Background and Aims

The use of Pembrolizumab, a selective humanized IgG4 kappa monoclonal antibody that inhibits the programmed death-1 receptor, has been largely accepted, especially in a series of trials in patients with advanced melanoma and in other cancers such as renal cell carcinoma (RCC), lymphoma and others. However, few recent studies demonstrated that Pembrolizumab promotes several renal dysfuncion such as acute tubular injury, acute interstitial nephritis and minimal change disease. To better elucidate this topic, we analyzed the renal function’s aspects from the PURE-01 protocol’s data, a phase 2, open label study of neoadjuvant Pembrolizumab before radical cystectomy (RC) for muscle invasive urothelial bladder cancer (MIUB).

Method

PURE-01 study (NCT02736266) enrolled preliminary 143 patients (pts). Eligibility criteria included: T2-T4N0 stage and residual disease after transurethral reduction of bladder. Pts received 3 cycles of Pembrolizumab 200 mg 3 weekly before RC. Computed tomography scan, FDG-PET/CT scan, and bladder multipara metric magnetic resonance imaging were performed during screening and before RC. Radiologically non-responders to pembro (per investigator decision) are given 3 additional courses of dose-dense MVAC chemotherapy. The collected data consisted in: the serum creatinine at baseline, after the first, second and last cycle in order to obtain the renal function by using eGFR formula (CKD-EPI-2009) for each time step; urine test analysis data after each cycle; the T stage from cTNM (AJCC TNM system-2019) before the treatment; clinical data such as presence of Diabetes, Hypertension, Hydronephrosis, BMI. The main outcome of the study was to correlate the renal function variation (from the pre-treatment to each treatment cycle) with the other clinical variables. Data analysis were performed using linear model, Kruskal-Wallis test and Wilcoxon test with holm’s correction.

Results

The median age of the patients was 68 years (62-73), with the 13% of the pts as female. We observed the presence of Hypertension, Hydronephrosis, Diabetes, Overweight (BMI≥25 and BMI&lt;30) and Obesity (BMI≥30) respectively at 54%, 20%, 22%, 50% and 10% in the total population. According pre-treatment T stage we divided the cohort as follows: 17% with stage 0, 32% with stage 2, 47% with stage 3 and 4% with stage 4. The renal function of pts according to the CKD classification was: 26% as stage I (≥90 mL/min/1.73 m2), 55% as stage II (&lt;90 mL/min/1.73 m2 and ≥60 mL/min/1.73 m2), 11% as stage IIIa (&lt;60 mL/min/1.73 m2 and ≥45 mL/min/1.73 m2) and 8% as stage IIIb-IV-V (&lt;45 mL/min/1.73 m2). We observed that eGFR after the first, second and last cycle, remained stable from the pre treatment values, with a median variation of respectively +1.45 (IQR -2.32,6.46), +1.35 (IQR -2.42, 6.74) and +1.75 (-2.83, 6.5) mL/min/1.73 m2 and without the onset of nephrotic-range proteinuria. Considering the variation after the first cycle, a significative positive correlations were found with the presence of hydronephrosis (+4.4 mL/min/1.73 m2, CI = 0.9:7.9, p=0.02), T stage 3 (+4.5, CI= 0.7:8.3, p=0.02) and T stage 4 (+14.8, CI=7.0:22.6, p=0.0003); after the second cycle we observed positive correlation with T stage 4 (+8.6, CI=0.5:16.8, p=0.04); after the last cycle the variation correlated with hydronephrosis (+4.2, CI=0.5:7.8, p=0.03) and T stage 4 (+10.7, CI=2.2:19.1, p=0.02).

Conclusion

We observed that the treatment with neoadjuvant pembrolizumab, in patients with bladder cancer, does not correlate with a decay of eGFR, but on the contrary, from our data, is associated with a small improvement of renal function, especially for those patients who presented higher stage of T and hydronephrosis before the treatment suggesting the Permbrolizumab’s safety in neoadjuvant therapy before RC for MIUBC from the nephrological point of view. This results needs more in-depths studies to be confirmed.