Pembrolizumab as Neoadjuvant Therapy Before Radical Cystectomy in Patients With Muscle-Invasive Urothelial Bladder Carcinoma (PURE-01): An Open-Label, Single-Arm, Phase II Study

Abstract

Purpose To determine the activity of pembrolizumab as neoadjuvant immunotherapy before radical cystectomy (RC) for muscle-invasive bladder carcinoma (MIBC) for which standard cisplatin-based chemotherapy is poorly used. Patients and Methods In the PURE-01 study, patients had a predominant urothelial carcinoma histology and clinical (c)T≤3bN0 stage tumor. They received three cycles of pembrolizumab 200 mg every 3 weeks before RC. The primary end point in the intention-to-treat population was pathologic complete response (pT0). Biomarker analyses included programmed death-ligand 1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 pharmDx assay), genomic sequencing (FoundationONE assay), and an immune gene expression assay. Results Fifty patients were enrolled from February 2017 to March 2018. Twenty-seven patients (54%) had cT3 tumor, 21 (42%) cT2 tumor, and two (4%) cT2-3N1 tumor. One patient (2%) experienced a grade 3 transaminase increase and discontinued pembrolizumab. All patients underwent RC; there were 21 patients with pT0 (42%; 95% CI, 28.2% to 56.8%). As a secondary end point, downstaging to pT<2 was achieved in 27 patients (54%; 95% CI, 39.3% to 68.2%). In 54.3% of patients with PD-L1 CPS ≥ 10% (n = 35), RC indicated pT0, whereas RC indicated pT0 in only 13.3% of those with CPS < 10% (n = 15). A significant nonlinear association between tumor mutation burden (TMB) and pT0 was observed, with a cutoff at 15 mutations/Mb. Expression of several genes in pretherapy lesions was significantly different between pT0 and non-pT0 cohorts. Significant post-therapy changes in the TMB and evidence of adaptive mechanisms of immune resistance were observed in residual tumors. Conclusion Neoadjuvant pembrolizumab resulted in 42% of patients with pT0 and was safely administered in patients with MIBC. This study indicates that pembrolizumab could be a worthwhile neoadjuvant therapy for the treatment of MIBC when limited to patients with PD-L1–positive or high-TMB tumors.

The Quest for an Ideal Neoadjuvant Systemic Therapy in Cisplatin-Ineligible Patients with Muscle-Invasive Localized Urothelial Carcinoma

“…However, 19 out of 21 patients with pCR had a PD‐L1 combined positive score of ≥10. The study met its primary endpoint of pT0 ≥25% . These results are encouraging, as the pCR with single‐agent pembrolizumab appears comparable to 38% pCR with neoadjuvant conventional‐dose MVAC, although it warrants investigation in larger randomized trials .…”

“…The study met its primary endpoint of pT0 ≥25% . These results are encouraging, as the pCR with single‐agent pembrolizumab appears comparable to 38% pCR with neoadjuvant conventional‐dose MVAC, although it warrants investigation in larger randomized trials . Similarly, in the single‐arm phase II ABACUS trial, two doses of neoadjuvant atezolizumab resulted in pCR of 29% (20/68; 95% confidence interval [CI], 19%–42%) in cisplatin‐ineligible patients with T2–4N0M0 MIBC.…”

Outcomes of neoadjuvant chemotherapy using gemcitabine and cisplatin in muscle invasive bladder cancer: A retrospective analysis of the patient and treatment factors in a single institute

“…It is also postulated that the more “inflamed” tumour such as the luminal‐infiltrative subtype should respond better to immunotherapy. Necchi et al in a phase 2 study indicated that pembrolizumab could be a worthwhile neoadjuvant therapy for the treatment of MIBC when limited to patients with PD‐L1–positive or high‐TMB (tumour mutation burden). Research of using neoadjuvant and adjuvant immunotherapy with check point inhibitors are still ongoing, and patient recruitments into these trials are encouraged to shed more light into future clinical practice.…”

Bladder cancer, a unique model to understand cancer immunity and develop immunotherapy approaches

“…The FDA has approved pembrolizumab separately as second‐line therapy for post‐platinum and first‐line treatment for cisplatin ineligible patients with locally advanced/metastatic UC. Recently, the benefit of using pembrolizumab for prior radical cystectomy neoadjuvant therapy has been reported (see supplementary material, Table S1).…”

“…For bladder cancer, although the Ventana PD‐L1 assays have been FDA approved as biomarkers for atezolizumab (https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm501878.htm) and durvalumab (https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm555930) treatments, there is some degree of ambiguity in data from clinical studies for the correlation of PD‐L1 expression to therapeutic response and it has limited negative predictive value . TML, which is generally high in bladder cancer , has been correlated to bladder cancer anti‐PD‐1/PD‐L1 immunotherapy responses , although with an exception of a study with limited samples . TCGA subtype has been correlated to therapeutic response, but with conflicting messages from different studies .…”