Neoadjuvant Gemcitabine and Split-Dose Cisplatin Plus Pembrolizumab Provides Safe and Successful Downstaging Strategy for Muscle-Invasive Bladder Cancer

Patients with muscle-invasive bladder cancer treated with gemcitabine and split-dose cisplatin plus pembrolizumab experienced improved pathological downstaging.

Treatment with neoadjuvant gemcitabine (Gemzar), split-dose cisplatin, and pembrolizumab (Keytruda) prior to radical cystectomy resulted in improved pathologic downstaging in patients with T2-4aN0/XM0 muscle-invasive bladder cancer, according to the results of a phase 2 study (NCT02690558).

Findings from the study indicated that investigators reported a pathologic downstaging rate of 56% (n = 22; 95% CI, 40%-72%) and 36% (n = 14) achieved a pathological complete response (95% CI, 21%-53%). Additionally, 1 of 6 patients who were administered the pembrolizumab lead in had pathologic downstaging. Out of the 27 patients who received all 4 cycles of treatment, 70% (n = 19) had pathologic downstaging. Patients with T3 or T4 disease had a 45% (n = 5) of pathological downstaging.

“Our study is the first to demonstrate a similarly robust rate of pathologic downstaging in the setting of split-dose cisplatin, a regimen that is more tolerable and accessible to patients with limited renal function,” investigators of the study wrote.

A total of 39 patients enrolled on the study, 26% (n = 10) of whom had node-positive disease at the time of cystectomy and 1 patient with T3b disease was diagnosed as being metastatic.

Investigators reported that 38 patients underwent cystectomy, with the median time to cystectomy of 46 days following completion of protocol therapy. All but 2 patients had completed therapy within 12 weeks. A total of 5% (n = 2) of patients had positive margins for invasive urothelial cancer, and 2 patients had margins for noninvasive urothelial cancer.

The study had a median follow-up of 15.7 months, wherein 21% (n = 8) of patients relapsed, 6 of whom had node-positive disease at time of the cystectomy. During follow-up, 23% (n = 9) of patients died, with 7 deaths being disease related. Notably, no deaths were related to treatment.

Additional findings from the trial indicated that the 1-year event-free survival (EFS) was 89%. Moreover, the 1-year recurrence-free survival (RFS) and overall survival (OS) were 75%, and 91%, respectively. Notably, the medians EFS, RFS, and OS have not yet been reached. For those patients who achieved pathologic downstaging, a significantly longer RFS was reported compared with those without downstaging (median, not reached vs 10.9; HR, 0.13; 95% CI, 0.03-0.59; log-rank P =.009).

Among the patients who received pembrolizumab lead in, 4 stopped treatment due to grade 3 or 4 AEs such as neutropenia, thrombocytopenia, and febrile neutropenia. Those who stopped treatment had worsening renal function, which investigators attributed to possible treatment with cisplatin. Among the 33 other patients who were treated without the lead-in dose of pembrolizumab and given split-dose cisplatin, 76% (n = 25) completed 4 cycles of treatment, and 23% (n = 9) had dose reductions due to AEs.

Although 1 patient experienced new-onset type 1 diabetes mellitus with ketoacidosis related to pembrolizumab, however, no patients required steroids for immune-related AEs. Additionally, 1 patient developed myelodysplastic syndrome 1-year following cystectomy, which was thought to be treatment-related. Additionally, 1 patient experienced cardiac arrest with a pulmonary embolus and myocardial infraction 1 month after cystectomy, although this was not thought to be related to treatment. There were no treatment-related deaths.

The most common any grade adverse effects (AEs) included thrombocytopenia (74%), anemia (69%), neutropenia (67%), and hypomagnesemia (67%).

In terms of patient-reported outcomes, the most common grade 3 or higher AEs included fatigue (31%), aching muscles (18%), pain (15%), nausea (13%), and shortness of breath (13%). Investigators reported lower grade AEs vs patients (62%), and only over-reported 1% of the time.


Rose TL, Harrison MR, Deal AM, et al. Phase II study of gemcitabine and split-dose cisplatin plus pembrolizumab as neoadjuvant therapy before radical cystectomy in patients with muscle-invasive bladder cancer. J Clin Oncol. Published online August 24, 2021. doi:10.1200/JCO.21.01003

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