Presentation Authors: Hristos Kaimakliotis*, Costantine Albany, Indianapolis, IN, Jean Hoffman-Censits, Edouard Trabulsi, W. Kevin Kelly, Philadelphia, PA, Joel Picus, St. Louis, MO, Nabil Adra, Clint Cary, Michael Koch, Indianapolis, IN, Mark Fleming, Norfolk, VA, Radhika Walling, Indianapolis, IN, J. Luke Godwin, Kenilworth, NJ, Robert Abouassaly, Matthew Cooney, Pingfu Fu, Ariel Nelson, Cleveland, OH, Ginu Xavier, Indianapolis, IN, Lee Ponsky, Christopher Hoimes, Cleveland, OH
Introduction: We sought to assess if pembrolizumab (pembro) improves the pathologic response rate in locally advanced urothelial carcinoma (UC) when combined with gemcitabine (G) and cisplatin (C) neoadjuvant chemotherapy (NAC) through a multicenter phase 1b/2 chemo-immunomodulation trial. Historically, the best pathologic non-muscle invasive rate (PaIR, â‰¤pT1N0M0) has been noted for neoadjuvant dose dense MVAC at ~44%.
Methods: Cisplatin eligible patients with cT2-4aN0M0 UC were treated with pembro 200mg q3wks on day 8 for 5 doses; with C (70mg/m2) day 1, and G (1000mg/m2) days 1 and 8 of a 21-day cycle, for 4 cycles; followed by radical cystectomy (RC). Minimum criteria for evaluation of safety was one dose pembro and for efficacy two doses and RC. The primary endpoint was PaIR of â‰¥48%, and secondary endpoints included safety and tolerability, RC rate, relapse free-, disease specific-, and overall survival.
Results: Forty patients (pts) were accrued: median age was 65 years, 75% were male, 10% had mixed UC histology, and PD-L1 combined positive score â‰¥10 was 52%. No dose-limiting toxicities were noted in the 6 pts on phase 1b. Average number of doses given (vs intended) for pembro=4.3(5), C=3.7(4), G=7.2(8). There was 1 death on post-RC day 9 due to mesenteric ischemia. One pt did not have RC due to adverse event (AE), gr4 thrombocytopenic purpura; UC in remission at 14mo, and 3 patients refused RC. One pt with presumed gr3 MI during cycle 4 had a negative cardiac workup and completed therapy and RC without further AE. One gr4 hyponatremia and ten gr3 events did not preclude RC (2-each thromboembolism, elevated creatinine, hyponatremia;1-each: dehydration, emesis, neutropenic fever, infection). Gr 3/4 cytopenias occurred in 57% of pts.Of 36 pts who had RC the median time to surgery was 5.3 wks from last dose. Baseline stage was cT2 51%, cT3 44%, cT4a 5%. The PaIR was 61%. Sixteen pts were downstaged to pT0 (44.4%), 3 to pTis (8.3%), and 3 to pT1 (8.3%). PaIR did not correlate with baseline PD-L1 score. At 17.4 (1.6-33.3) months median follow up, the relapse free-, overall-, and disease specific-survival, was 70%, 81%, and 90%, respectively.
Conclusions: Neoadjuvant chemo-immunotherapy with pembro in locally advanced UC has manageable toxicity, a comparable time to surgery as NAC, and has improved pathologic outcomes compared to historic controls. Furthermore, the long-term effects of immunotherapy with a sustained high disease specific survival may provide control rates that warrant further study. _x000D_
Clinical trial identificationClinicaltrials.gov: NCT02365766
Source of Funding: Hoosier Cancer Research Network