Neoadjuvant pembrolizumab induces pathologic response in bladder cancer
CHICAGO — Neoadjuvant pembrolizumab induced pathologic complete responses among nearly 40% of patients with urothelial bladder cancer, according to interim results of the PURE-01 trial presented at the ASCO Annual Meeting.
Also, neoadjuvant pembrolizumab (Keytruda, Merck) appeared safe and did not delay surgery.
Most patients with muscle-invasive bladder cancer — which has a high metastatic rate — have high-risk disease and require systemic treatments. Pembrolizumab is FDA approved for metastatic urothelial bladder cancer after failure on platinum-based therapy or for cisplatin-ineligible patients.
For the open-label, single-arm, phase 2 PURE-01 trial, Andrea Necchi, MD, medical oncologist at Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, and colleagues evaluated the efficacy, safety and immune modulatory effects of preoperative pembrolizumab among patients with T2 to T3bN0 stage and residual disease after transurethral resection of the bladder.
In the first stage of the trial, 43 enrolled patients (median age, 66 years; 81.4% men) received 200 mg pembrolizumab every 3 weeks for three cycles before radical cystectomy.
Pathologic complete response among intention-to-treat patients served as the primary endpoint.
Researchers observed a pathologic complete response among 39.5% (95% CI, 26.3-54.4) of treated patients, and pathologic downstaging to pT<2 occurred among 51.2%.
The most common adverse events included hyperthyroidism, hypothyroidism, alanine aminotransferase/aspartate aminotransferase increase, pruritus and pyrexia.
One patient discontinued pembrolizumab due to grade 3 alanine aminotransferase increase.
Median total hospital length of stage was 15.5 days (interquartile range [IQR], 11.7-20).
Researchers assessed PD-L1 expression in samples of transurethral resection of the bladder using combined positive score and observed a median score of 20% (IQR, 6-50).
Median combined positive score was 30% among patients with a pathologic complete response vs. 10% among those without a pathologic complete response (P = .0549).
Mean tumor mutational burden was 11.2 mut/Mb (IQR, 6.6-14) overall and higher among patients with a pathologic complete response, but the difference did not reach statistical significance (13.16 mut/Mb vs. 11.41 mut/Mb).
Gene expression data were consistent with promotion of adaptive immunity in matched tumor samples from nonresponding patients, Necchi noted.
In an analysis of 18 matched pre- and post-tissue samples, median combined positive score increased from baseline to after treatment (10% vs. 30%), although the difference was not significant, whereas tumor mutational burden decreased (10.1 mut/Mb vs. 4.4 mut/Mb; P = .0036).
Pathologic complete response rate increased to 50% among 22 patients with a PD-L1 combined positive score of at least 20%, to 60% among 25 patients with deleterious DNA damage response and/or RB1 genomic alterations, and to 90% among 10 patients with all these features.
“Deleterious DNA damage response, RB1 genomic alterations and PD-L1 combined positive score may constitute the algorithm for selecting patients who deserve a bladder-sparing approach after response assessment,” Necchi said. – by Jennifer Southall
Necchi A, et al. Abstract 4507. Presented at: ASCO Annual Meeting; June 1-5, 2018; Chicago.
Necchi A, et al. J Clin Oncol. 2018;doi:10.1200/JCO.2018.36.6_suppl.TPS533.
Disclosures: Necchi reports consultant/advisory roles with AstraZeneca, Bayer, Clovis Oncology, Merck Sharp & Dohme and Roche; research funding from Amgen, AstraZeneca and Merck Sharp & Dohme; and travel, accommodations or expenses from Merck Sharp & Dohme, Pierre Fabre and Roche. Please see the abstract for all other authors’ relevant financial disclosures.