Groundbreaking Results With Pembrolizumab Plus Surgery in Bladder Cancer

The PURE-01 study showed that neoadjuvant pembrolizumab before surgery could downstage disease in muscle-invasive bladder cancer patients.

Neoadjuvant pembrolizumab was safe to administer and resulted in a significant proportion of patients with muscle-invasive bladder cancer (MIBC) presenting at radical cystectomy with pT0 disease, according to a new study. The benefit was mostly seen in patients with programmed death ligand 1 (PD-L1)–positive tumors, or those with high tumor mutation burden.

Recommended treatment for MIBC includes radical cystectomy (RC) preceded by neoadjuvant chemotherapy in cisplatin-eligible patients. “However, neoadjuvant chemotherapy has failed to become a widely used treatment for MIBC, as it is administered in only 20% of eligible patients,” wrote study authors led by Andrea Necchi, MD, of the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy. “Approximately 50% of patients are ineligible to receive cisplatin as a result of established preexisting contraindications, and a subset of patients refuse to receive any chemotherapy.”

The PURE-01 study included 50 patients with MIBC, regardless of cisplatin eligibility. They received 3 cycles of the immune checkpoint inhibitor pembrolizumab every 3 weeks prior to RC. The results were published in the Journal of Clinical Oncology.

The median age in the study was 66 years, and 82% of the patients were male. A majority of patients had a clinical T stage of T3N0 (54%), followed by T2N0 (32%) and T2-3N1 (4%). Most patients received 3 cycles of pembrolizumab (94%).

All patients underwent RC. Of those, 21 patients (42%) achieved a pT0 stage, which the authors described as “unprecedented.” Six patients had residual pTa (3 patients), pTis (2 patients), or pT1 (1 patient) tumors; this resulted in a total of 27 patients (54%) being downstaged to non–muscle-invasive tumors. Ten patients had pathologic lymph node involvement, and five had treatment failure (four had lack of a radiologic response, and one discontinued pembrolizumab due to transaminitis).

Among 35 patients deemed to be PD-L1 positive, pT0 was achieved in 19 patients (54.3%), compared with only 13.3% of those who were PD-L1 negative (P = .011). A significant association was also seen between pT0 response and tumor mutation burden, and authors wrote that a meaningful cutoff would correspond to the 80th quantile for mutation burden.

The most frequent all-grade adverse event was thyroid dysfunction, in 9 patients (18%). Three patients (6%) had grade 3 adverse events, only one of which led to discontinuation of the therapy. Postsurgical complications were similar to those seen in previous reports of RC.

“These results will encourage the clinical development of new neoadjuvant therapies and allow for more patients with MIBC to receive multimodality therapy,” the authors concluded. “Pending the results of the next randomized studies, pembrolizumab may now be considered an option for cisplatin-ineligible patients with a PD-L1–expressing or high tumor mutation burden tumor.”

Paul Mathew, MD, of Tufts Medical Center in Boston, who was not involved in the research, praised the “remarkably high” response rates seen with this therapy, and noted that those ongoing and future studies will still help in defining the role of biomarkers, including PD-L1 and others. “The fact that this therapy appears both effective and well-tolerated without significant impact on surgical eligibility will likely translate into a far higher adoption rate of neoadjuvant therapy in muscle-invasive urothelial carcinoma compared with the historically dismal rates with chemotherapy,” Mathew told Cancer Network.