(UroToday.com) For patients with muscle-invasive bladder cancer who are eligible for curative-intent treatment, cisplatin-based neoadjuvant chemotherapy followed by radical cystectomy (RC) is a standard of care with improved pathologic response and overall survival (OS) compared to RC alone. However, recurrence rates, progression, and cancer-related death remain relatively high. Pembrolizumab is active in high-risk non-muscle invasive and metastatic bladder cancer and is generally well tolerated. Thus, there was interest to add pembrolizumab to existing neoadjuvant chemotherapy regimes. As reported in a plenary abstract presentation in the Rapid Abstract Session: Urothelial Carcinoma and Rare Tumors session at the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), Dr. Rose and colleagues did just that, performing a phase II trial evaluating the safety and efficacy of gemcitabine and split-dose cisplatin (GC) + pembrolizumab as neoadjuvant therapy prior to RC (NCT02690558).
The authors enrolled patients with clinical T2-4a N0/X M0 urothelial carcinoma of the bladder who were eligible for RC. As neoadjuvant therapy, patients received pembrolizumab 200mg on day 1 with cisplatin 35mg/m2 and gemcitabine 1000mg/m2 on days 1 and 8 every 3 weeks for 4 cycles, followed by RC within 4-8 weeks. The first 6 patients received full-dose cisplatin (70mg/m2 on day 1) and a lead-in pembrolizumab dose; however, this schedule was discontinued for excess toxicity. 
The authors sought primarily to assess pathologic downstaging rate (< pT2; NMIBC) with the null and alternative hypothesis rates of 35% and 55%, respectively. Secondary endpoints included toxicity, pT0 rate, event-free survival, and OS with further exploratory objectives including the association of response with molecular subtype and post-treatment changes in the immune microenvironment (predicted neoantigens, immune gene expression, and T cell receptor repertoire.
The authors enrolled 39 patients (72% cT2, 23% cT3, 5% cT4a) between May 2016 and July 2020. The median age of enrolled patients was 66 years and 82% were male.
Patients received a median of 4 cycles of therapy. All patients moved forward with RC, except one who declined but is included in the intention to treat analysis. 
The rate of pathological downstaging (< pT2N0) was 56% (22/39) and pT0N0 rate was 36% (14/39). The most common adverse events (AEs) of any grade were thrombocytopenia (n=29; 74%), anemia (n=27; 69%), neutropenia (n=26; 67%), and hypomagnesemia (n=26; 67%). Most common serious (grade 3 or 4) AEs were neutropenia (n=16; 41%), thrombocytopenia (n=13; 33%), febrile neutropenia (n=5; 13%), and anemia (n=4; 10%). A single patient had new onset type 1 diabetes mellitus event with ketoacidosis related to pembrolizumab. Nine patients (23%) discontinued neoadjuvant therapy due to AEs, including 4 of the 6 patients who received full-dose cisplatin with pembrolizumab lead-in.
Pathologic response rates did not significantly differ on the basis of PD-L1 status (p=0.25).
Survival data are not yet mature and correlative studies are ongoing.
In conclusion, the authors found that neoadjuvant GC + pembrolizumab was generally safe and met the primary endpoint for improved pathologic downstaging. This approach is currently being evaluated in the ongoing phase III KEYNOTE-866.
Presented by: Tracy L. Rose, MD, MPH, The University of North Carolina Chapel Hill School of Medicine and UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina
Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center, Contact: @WallisCJD on Twitter during the 2021 American Society of Clinical Oncology Genitourinary Cancers Symposium (#GU21), February 11th-February 13th, 2021