Preoperative pembrolizumab (pembro) before radical cystectomy (RC) for muscle-invasive urothelial bladder carcinoma (MIUC): Interim clinical and biomarker findings from the phase 2 PURE-01 study.

Necchi, Andrea; Briganti, Alberto; Bianchi, Marco; Raggi, Daniele; Giannatempo, Patrizia; Lucianò, Roberta; Colecchia, Maurizio; Massa, Simona; Bandini, Marco; Fossati, Nicola; Gandaglia, Giorgio; Colombo, R.; Gallina, Andrea; Salonia, Andrea; Salvioni, Roberto; Ali, Siraj M.; Ross, Jeffrey S.; Chung, Jon; Montorsi, Francesco

doi:10.1200/jco.2018.36.15_suppl.4507

Cited by 15 publications

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“…Chalmers and colleagues have reported that a proportion of tumors across multiple cancer types have high TMB, showing that TMB has broad clinical validity as a biomarker. Figure illustrates a timeline of the emergence of TMB as a biomarker.…”

Section: Tmb As a Predictive Biomarkermentioning

confidence: 99%

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Tumor Mutational Burden as a Predictive Biomarker for Response to Immune Checkpoint Inhibitors: A Review of Current Evidence

Fabrizio²,

et al. 2019

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Treatment with immune checkpoint inhibitors (ICPIs) extends survival in a proportion of patients across multiple cancers. Tumor mutational burden (TMB)—the number of somatic mutations per DNA megabase (Mb)—has emerged as a proxy for neoantigen burden that is an independent biomarker associated with ICPI outcomes. Based on findings from recent studies, TMB can be reliably estimated using validated algorithms from next‐generation sequencing assays that interrogate a sufficiently large subset of the exome as an alternative to whole‐exome sequencing. Biological processes contributing to elevated TMB can result from exposure to cigarette smoke and ultraviolet radiation, from deleterious mutations in mismatch repair leading to microsatellite instability, or from mutations in the DNA repair machinery. A variety of clinical studies have shown that patients with higher TMB experience longer survival and greater response rates following treatment with ICPIs compared with those who have lower TMB levels; this includes a prospective randomized clinical trial that found a TMB threshold of ≥10 mutations per Mb to be predictive of longer progression‐free survival in patients with non‐small cell lung cancer. Multiple trials are underway to validate the predictive values of TMB across cancer types and in patients treated with other immunotherapies. Here we review the rationale, algorithm development methodology, and existing clinical data supporting the use of TMB as a predictive biomarker for treatment with ICPIs. We discuss emerging roles for TMB and its potential future value for stratifying patients according to their likelihood of ICPI treatment response. Implications for Practice Tumor mutational burden (TMB) is a newly established independent predictor of immune checkpoint inhibitor (ICPI) treatment outcome across multiple tumor types. Certain next‐generation sequencing‐based techniques allow TMB to be reliably estimated from a subset of the exome without the use of whole‐exome sequencing, thus facilitating the adoption of TMB assessment in community oncology settings. Analyses of multiple clinical trials across several cancer types have demonstrated that TMB stratifies patients who are receiving ICPIs by response rate and survival. TMB, alongside other genomic biomarkers, may provide complementary information in selecting patients for ICPI‐based therapies.

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Section: Tmb As a Predictive Biomarkermentioning

confidence: 99%

“…As mentioned above, PD‐L1 expression and TMB have not been significantly correlated in most ICPI studies (Table ). Reported and ongoing clinical trials and observational studies that have analyzed or will analyze TMB outcomes are summarized in Table , Table , and Table .…”

Section: Summary Of Outcomes Associated With Tmbmentioning

confidence: 99%

Tumor Mutational Burden as a Predictive Biomarker for Response to Immune Checkpoint Inhibitors: A Review of Current Evidence

Fabrizio²,

et al. 2019

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“…Complete pathologic response rates observed with split schedule cisplatin in this study (17.5%) are similar to those in a recent multicenter, prospective trial of dose-dense GC (15%) in which patients received gemcitabine 2,500 mg/m 2 on day 1 and cisplatin 35 mg/m 2 on days 1 and 2 every 2 weeks [7]. However, these response rates should be viewed within the context of historical response rates from transurethral resection alone with immediate cystectomy (15%) [2], ddMVAC using CS cisplatin (26%-43%) [8], and from neoadjuvant immunotherapy (29%-32%) [9,10].…”

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confidence: 99%

Efficacy of Split Schedule Versus Conventional Schedule Neoadjuvant Cisplatin-Based Chemotherapy for Muscle-Invasive Bladder Cancer

et al. 2019

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Neoadjuvant cisplatin‐based chemotherapy (NAC; 70 mg/m2) is standard of care for muscle‐invasive bladder carcinoma (MIBC). Many patients (pts) cannot receive cisplatin because of renal impairment, and administration of cisplatin 35 mg/m2 on day 1 + 8 or 1 + 2 (i.e., split schedule) is a commonly used alternative. In this retrospective analysis, we compared complete (pT0) and partial (

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“…Mutations in DNA damage and repair (DDR) genes may predict responses both to chemotherapy 126,127 and immunotherapy 128–131 in patients with UC. Perhaps, patients with defects in this pathway could benefit from a combination strategy.…”

Section: Role Of Chemotherapy In the Immunotherapy Eramentioning

confidence: 99%

The continuing role of chemotherapy in the management of advanced urothelial cancer

Liaño

Durán

2018

Therapeutic Advances in Urology

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Despite intense drug development in the last decade in metastatic urothelial carcinoma and the incorporation of novel compounds to the treatment armamentarium, chemotherapy remains a key treatment strategy for this disease. Platinum-based combinations are still the backbone of first-line therapy in most cases. The role of chemotherapy in the second line has been more ill-defined due to the complexity of this setting, where patient selection remains critical. Nevertheless, two regimens, one in monotherapy (i.e. vinflunine) and one in combination with antiangiogenics (i.e. docetaxel + ramucirumab) have shown efficacy. Immunotherapy through checkpoint inhibition has revealed remarkably durable benefit in a small proportion of patients in the first and second line and is currently the preferred partner for combinations with chemotherapy. Difficult populations such as patients with liver metastases or those progressing to checkpoint inhibition represent a medical challenge and selective ways of delivering cytotoxics, like the antibody–drug conjugates, might represent a valid alternative. This article reviews the current role of chemotherapy in the management of advanced urothelial carcinoma and the ongoing and coming studies involving this treatment strategy.

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Preoperative pembrolizumab (pembro) before radical cystectomy (RC) for muscle-invasive urothelial bladder carcinoma (MIUC): Interim clinical and biomarker findings from the phase 2 PURE-01 study.

Cited by 15 publications

References 0 publications

Tumor Mutational Burden as a Predictive Biomarker for Response to Immune Checkpoint Inhibitors: A Review of Current Evidence

Tumor Mutational Burden as a Predictive Biomarker for Response to Immune Checkpoint Inhibitors: A Review of Current Evidence

Efficacy of Split Schedule Versus Conventional Schedule Neoadjuvant Cisplatin-Based Chemotherapy for Muscle-Invasive Bladder Cancer

The continuing role of chemotherapy in the management of advanced urothelial cancer

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