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PURE-01 Trial: Neoadjuvant Immunotherapy in Muscle-Invasive Bladder Carcinoma

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Key Points

  • Complete pathologic response was observed in 42% of patients, with most occurring in patients with PD-L1 CPS ≥ 10%.
  • Higher tumor mutation burden was associated with increased likelihood of pT0.

In the Italian phase II PURE-01 trial reported in the Journal of Clinical Oncology, Necchi et al found that neoadjuvant pembrolizumab (Keytruda) before radical cystectomy in muscle-invasive bladder carcinoma produced complete pathologic response (pT0) in 42% of patients, with pT0 being more common in patients with higher programmed cell death ligand 1 (PD-L1) expression.

In the study, 50 patients from two sites in Milan were enrolled between February 2017 and March 2018 and received three cycles of pembrolizumab at 200 mg every 3 weeks before radical cystectomy. Patients had a predominant urothelial carcinoma histology and clinical (c)T≤3bN0 stage tumors. Overall, 27 patients (54%) had cT3 tumors, 21 (42%) had cT2 tumors, and 2 (4%) had cT2-3N1 tumors.

Treatment Outcomes

All patients underwent radical cystectomy. Complete pathologic response was observed in 21 patients (42%), with downstaging to pT<2 being observed in 27 (54%). Among 35 patients with PD-L1 combined positive score (CPS) ≥ 10%, pT0 was achieved in 19 (54.3%), compared with 2 (13.3%) of 15 with CPS < 10%.

A significant (P = .022) nonlinear association between higher tumor mutation burden (TMB) and pT0 was observed that suggested a cutoff value of 15 mutations per megabase. No correlation between PD-L1 expression and TMB was observed. Gene expression analysis showed that 18 of 22 evaluated genes from pT0 patients had significantly higher expression in pretherapy lesions compared with pretherapy lesions from pT≥2 patients. Marked posttherapy changes in TMB and adaptive mechanisms of immune resistance were found in residual tumors.

The most frequent adverse event of any grade during pembrolizumab treatment was thyroid dysfunction (18%); 3 patients had grade 3 adverse events, resulting in treatment discontinuation in 1 (transaminase elevation). Delayed immune-related adverse events included pyrexia (6%), pruritus (6%), and xerostomia (4%).

The investigators concluded, “Neoadjuvant pembrolizumab resulted in 42% of patients with pT0 and was safely administered in patients with [muscle-invasive bladder carcinoma]. This study indicates that pembrolizumab could be a worthwhile neoadjuvant therapy for the treatment of [muscle-invasive bladder carcinoma] when limited to patients with PD-L1–positive or high-TMB tumors.”

The study was supported by Merck and a grant from Associazione Italiana per la Ricerca sul Cancro.

Andrea Necchi, MD, of the Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, is the corresponding author for the Journal of Clinical Oncology article.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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