Neoadjuvant pembrolizumab regimen shows benefit in MIBC

Neoadjuvant treatment with pembrolizumab (Keytruda) plus gemcitabine and cisplatin showed promise in patients with muscle-invasive bladder cancer (MIBC), according to findings from a phase 2 study published in the Journal of Clinical Oncology.1,2

The study enrolled patients with clinical T2-4aN0/XM0 MIBC who were eligible for radical cystectomy. Overall, 56% of patients had pathologic downstaging (<pT2N0) and 36% of patients had a pathologic complete response (pCR; pT0N0M0).

“Downstaging, or treating tumors so that they become less invasive prior to surgical removal, is an important tool in muscle-invasive bladder cancer,” lead author Tracy Rose, MD, MPH, assistant professor at the UNC School of Medicine, UNC Lineberger Comprehensive Cancer Center, stated in a press release. “If we can treat a tumor presurgically so that it regresses to a stage where it is superficial and does not invade the bladder muscle wall, the chances of long-term survival are better.”

The study included 39 patients with a median age of 66 years (range, 45-82). Eighty-two percent of patients were male and 18% of patients were female. Ninety-seven percent of patients were White and 3% of patients were Black. Eighteen percent of patients were current smokers, 67% were former smokers, and 15% were never smokers. The clinical stage at enrollment was T2 for 72% of patients, T3 for 23% of patients, and T4a for 5% of patients.

Eighteen percent of patients had previous non–muscle invasive bladder cancer, 79% of patients did not, and prior status was unknown for 3%. Five patients had prior BCG. Seventy-two percent of patients had an ECOG performance score of 0 and 28% had a score of 1. Regarding histology, 28 patients had pure urothelial disease, 7 patients had urothelial with squamous cell disease, and 1 patient each had urothelial with micropapillary, sarcomatoid, signet ring, and

glandular and squamous.

Overall, 22 (56%) patients reached <pT2N0 with the triplet regimen and 14 (36%) reached a pCR at pT0N0. PD-L1 status did not have a significant impact on pathologic downstaging.

There was a numerical, but not a statistically significant, difference in the downstaging rate between PD-L1–positive and –negative patients (67% vs 47%, respectively; P = .25).

“More than a third of the patients saw a complete regression of their cancer and ultimately may not require surgical bladder removal,” stated Rose. “More studies will need to be done to identify who can safely avoid surgery. Several ongoing trials are investigating this bladder-sparing approach.”

The most common adverse events (AEs) across all grades were thrombocytopenia (74%), anemia (69%), neutropenia (67%), and hypomagnesemia (67%). New-onset type 1 diabetes mellitus with ketoacidosis considered to be related to pembrolizumab occurred in 1 patient. Steroids for immune-related AEs were not required for any of the patients.

“Optimal management of MIBC is a huge unmet need,” UNC Lineberger’s Matthew Milowsky, MD, the paper’s corresponding author and the George Gabriel and Frances Gable Villere Distinguished Professor of Bladder and Genitourinary Cancer Research, stated in the press release. “We think that the combination treatment used in our trial may improve outcomes compared with chemotherapy alone, with the aim of ridding micrometastatic disease so that even a modest improvement in response rates translates to higher cure rates.”

Ongoing randomized trials have been launched to confirm the efficacy demonstrated in this trial, including the phase 3 KEYNOTE-866 trial (NCT03924856) evaluating perioperative pembrolizumab plus neoadjuvant gemcitabine and cisplatin versus perioperative placebo plus neoadjuvant gemcitabine and cisplatin in patients with MIBC.


1. Chemotherapy plus immunotherapy before surgery is beneficial for invasive bladder cancer outcomes. Published online August 30, 2021. Accessed September 6, 2021.

2. 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 [published online ahead of print August 24, 2021]. J Clin Oncol. doi:0.1200/JCO.21.01003