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 European Society for Medical Oncology (ESMO) consensus conference on testicular cancer was held on 3–5 November 2016 in Paris, France. The conference included a multidisciplinary panel of 36 leading experts in the diagnosis and treatment of testicular cancer (34 panel members attended the conference; an additional two panel members [CB and K-PD] participated in all preparatory work and subsequent manuscript development). The aim of the conference was to develop detailed recommendations on topics relating to testicular cancer that are not covered in detail in the current ESMO Clinical Practice Guidelines (CPGs) and where the available level of evidence is insufficient. The main topics identified for discussion related to: (1) diagnostic work-up and patient assessment; (2) stage I disease; (3) stage II-III disease; (4) post-chemotherapy surgery, salvage chemotherapy, salvage and desperation surgery and special topics; and (5) survivorship and follow-up schemes. The experts addressed questions relating to one of the five topics within five working groups. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel. A consensus vote was obtained following whole-panel discussions, and the consensus recommendations were then further developed in post-meeting discussions in written form. This manuscript presents the results of the expert panel discussions, including the consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

Background The efficacy and safety of a combination of chemotherapeutic agent compared with single-agent chemotherapy in the second-line setting of advanced urothelial carcinoma (UC) are unclear. We aimed to study the survival impact of single-agent compared with doublet chemotherapy as second-line chemotherapy of advanced UC. Patients and methods Literature was searched for studies including single-agent or doublet chemotherapy in the second-line setting after platinum-based chemotherapy. Random-effects models were used to pool trial-level data according to treatment arm, including median progression-free survival (PFS), overall survival (OS), objective response rate (ORR) probability, and grade 3–4 toxicity. Univariable and multivariable analyses, including sensitivity analyses, were carried out, adjusting for the percent of patients with ECOG performance status ≥1 and hepatic metastases. Results Forty-six arms of trials including 1910 patients were selected: 22 arms with single agent (n = 1202) and 24 arms with doublets (n = 708). The pooled ORR with single agents was 14.2% [95% confidence interval (CI) 11.1–17.9] versus 31.9% [95% CI 27.3–36.9] with doublet chemotherapy. Pooled median PFS was 2.69 and 4.05 months, respectively. The pooled median OS was 6.98 and 8.50 months, respectively. Multivariably, the odds ratio for ORR and the pooled median difference of PFS were statistically significant (P < 0.001 and P = 0.002) whereas the median difference in OS was not (P = 0.284). When including single-agent vinflunine or taxanes only, differences were significant only for ORR (P < 0.001) favoring doublet chemotherapy. No statistically significant differences in grade 3–4 toxicity were seen between the two groups. Conclusions Despite significant improvements in ORR and PFS, doublet regimens did not extend OS compared with single agents for the second-line chemotherapy of UC. Prospective trials are necessary to elucidate the role of combination chemotherapy, with or without targeted agents, in the salvage setting. Currently, improvements in this field should be pursued considering single-agent chemotherapy as the foundation for new more active combinations.

Outcomes of radiotherapy (RT) compared with chemotherapy (CT) remain poorly defined for clinical stage (CS) IIA and IIB seminoma. We aimed to evaluate the current role of the two treatment modalities in this setting of testicular seminoma. A systematic review and meta-analysis (MA) was carried out to identify all evaluable studies. Search was limited to studies published after 1990 and included the Medline, Embase databases, and abstracts from ASCO (GU), ESMO, AUA, and ASTRO meetings up to April 2014. Sensitivity analyses were applied including the following: CSIIA and CSIIB, paraortic + iliac RT only in both stages, RT dose (≥30 versus <30 Gy), and PEB/EP regimens only. Thirteen studies have been selected for MA on relapse outcome. No randomized trials compared RT and CT. There were 4 prospective and 9 retrospective studies, with a total of 607 patients receiving RT and 283 patients CT. The pooled relapse rate (RR) was similar between the RT [0.11, 95% confidence interval (CI) 0.08–0.14, P for heterogeneity = 0.096, I² = 38%] and CT groups (0.08, 95% CI 0.01–0.15, P for heterogeneity <0.001, I² = 82.5%). However, in the sensitivity analysis, the pooled RR for RT in CSIIB was 0.12 (95% CI 0.06–0.17) while it was 0.05 (95% CI 0–0.11) for CT. Long-term side-effects and incidence of second cancers were more frequently reported following RT. The overall incidence of nontesticular second malignancies was 0.04 (95% CI 0.01–0.02) in the RT group and 0.02 (95% CI 0.003–0.04) in the CT group. Although RT and CT appeared to be equal options in CSIIA and IIB seminoma, a trend in favor of CT for a lower incidence of side-effects and RR in CSIIB was found. This evidence is limited by the retrospective quality of studies and their small sample size.