Immunotherapy with PD-1 and PD-L1 inhibitors has become the standard of care for patients with advanced urothelial cancer who have progressed on or are ineligible for cisplatin-based therapy. The success of these agents in the metastatic setting has led to investigation in earlier stages of disease. For muscle-invasive bladder cancer (MIBC), the current standard of care is cisplatin-based chemotherapy followed by radical cystectomy (RC). However, only a small percentage of patients receive neoadjuvant chemotherapy, and as many as half of patients with MIBC are cisplatin-ineligible. An open-label, single arm, phase II trial (PURE-01) evaluated the PD-1 inhibitor pembrolizumab as neoadjuvant therapy (200 mg every 3 weeks for 3 cycles) prior to RC in 50 patients with MIBC.
All patients underwent RC following neoadjuvant pembrolizumb, with 21 (42%) achieving pathologic complete response (pT0). Additionally, 6 patients had residual tumor (pTa, pTis, or pT1), meaning 27 patients (54%) achieved pT<2 and were downstaged to nonmuscle invasive tumors. Biomarker analysis found an association between PD-L1 expression, tumor mutation burden (TMB), and gene expression with achieving pT0 . Patients with a PD-L1 combined positive score (CPS) ≥10% were more likely to achieve pT0 compared to patients with PD-L1 CPS <10% (54.3% vs 13.3%). TMB of ≥15 mutation/Mb was also significantly associated with increased rates of pT0 (P = .022). Patients achieving pT0 had significantly higher expression of genes related to interferon gamma signaling, antigen presentation, T-cell differentiation, chemokines and receptors, inhibitor receptors and ligands, and IDO1.
The most frequent adverse event (AE) of any grade was thyroid dysfunction (18%). Grade 3 AEs occurred in 3 patients (6%) and resulted in treatment discontinuation in one patient experiencing grade 3 transaminitis. Postsurgical complications were as expected, though some patients experienced delayed immune-related AEs, including pyrexia (6%), pruritus (6%), and xerostomia (4%).
The investigators concluded that pembrolizumab is safe for use as neoadjuvant therapy in patients with MIBC and is associated with an impressive rate of pT0, particularly in PD-L1-positive patients and patients with TMB scores ≥15 mutations/Mb. While future studies evaluating pembrolizumab in a randomized fashion are warranted, the authors stated that neoadjuvant pembrolizumab should be considered as an option in cisplatin-ineligible patients with PD-L1 expression or high TMB.