Neoadjuvant Gemcitabine and Split-Dose Cisplatin Plus Pembrolizumab for Muscle-Invasive Bladder Cancer

Get Permission

In a phase II study reported in the Journal of Clinical Oncology, Tracy L. Rose, MD, MPH, and colleagues found that neoadjuvant therapy with pembrolizumab, gemcitabine, and primarily split-dose cisplatin resulted in pathologic downstaging (< pT2N0) in more than half of patients undergoing radical cystectomy for muscle-invasive bladder cancer.

Tracy L. Rose, MD, MPH

Tracy L. Rose, MD, MPH

Study Details

In the U.S. multicenter trial, 39 eligible patients with clinical T2–4aN0/XM0 muscle-invasive disease were enrolled between June 2016 and March 2020. The first six patients received a single lead-in dose of pembrolizumab at 200 mg 2 weeks prior to pembrolizumab at 200 mg on day 1, cisplatin at 70 mg/m2 on day 1, and gemcitabine at 1,000 mg/m2 on days 1 and 8 every 21 days for four cycles. This schedule was discontinued for toxicity. Subsequent treatment (n = 33) eliminated lead-in pembrolizumab, with patients receiving pembrolizumab at 200 mg on day 1, split-dose cisplatin at 35 mg/m2 on days 1 and 8, and gemcitabine at 1,000 mg/m2 on days 1 and 8 every 21 days for four cycles.

The primary endpoint was pathologic downstaging (< pT2N0) with null and alternative hypothesis rates of 35% and 55%.

Pathologic Downstaging

All patients except one underwent radical cystectomy. Downstaging to < pT2N0 was achieved in 22 (56%, 95% confidence interval [CI] = 40%–72%) of 39 patients. Pathologic complete response was achieved in 14 (36%, 95% CI = 21%–53%). Downstaging was observed in 1 of 6 patients receiving the initial study regimen and in 21 (64%) of 33 receiving split-dose cisplatin and no pembrolizumab lead-in dose. Among 27 patients who completed all four cycles of treatment, downstaging was achieved in 19 (70%).

At a median follow-up of 15.7 months (interquartile range = 11.5–21.9 months), relapse had occurred in eight patients (21%), with six of these patients having node-positive disease at time of cystectomy. Median event-free, recurrence-free, and overall survival were not reached, with 1-year rates of 89%, 75%, and 91%, respectively. Patients with vs without pathologic downstaging had significantly better recurrence-free survival (median = not reached vs 10.9 months, hazard ratio = 0.13, 95% CI = 0.03–0.59, P = .009).


  • Pathologic downstaging to < pT2N0 was achieved in 56% of patients, with pathologic complete response in 36%.
  • Among patients completing four cycles of treatment, downstaging was achieved in 70%.

Adverse Events

The most common treatment-related adverse events of any grade were thrombocytopenia (74%), anemia (69%), neutropenia (67%), and hypomagnesemia (67%, all grade 1–2). Treatment-related grade ≥ 3 adverse events occurred in 74% of patients, the most commonly reported being neutropenia (40%) and thrombocytopenia (34%). One patient developed new-onset type 1 diabetes mellitus with ketoacidosis related to pembrolizumab; no patients required steroid treatment for immune-related adverse events.

Clinicians were found to consistently underreport adverse events compared with patients. On the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events, grade ≥ 3 adverse events reported by patients included fatigue in 31%, aching muscles in 18%, pain in 15%, nausea in 13%, and shortness of breath in 13%. Clinicians reported a lower grade of adverse events vs patients in 62% of cases and reported a higher grade in 1%.

The investigators concluded, “Neoadjuvant gemcitabine and cisplatin plus pembrolizumab met its primary endpoint for improved pathologic downstaging and was generally safe. A global study of perioperative chemotherapy plus pembrolizumab or placebo is ongoing [KEYNOTE-866, identifier: NCT03924856]).”

Matthew I. Milowsky, MD, of the Division of Oncology, University of North Carolina at Chapel Hill, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by Merck & Co. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.