Vesical Imaging-Reporting and Data System use predicting the outcome of neoadjuvant pembrolizumab in muscle-invasive bladder cancer.

OBJECTIVE: To evaluate the predictive capability of the pre- and post-pembrolizumab Vesical Imaging-Reporting and Data System (VI-RADS) to identify ypT0N0 or ypT≤1N0 response in muscle-invasive bladder cancer (MIBC) within the PURE-01 trial (ClinicalTrials.gov identifier: NCT02736266). PATIENTS AND METHODS: Patients were staged with bladder multiparametric magnetic resonance imaging (mpMRI) before and after treatment (three cycles of pembrolizumab) prior to radical cystectomy (RC). Logistic regression models were used to analyse the pre- and post- pembrolizumab VI-RADS against ypT≤1N0 and ypT0N0 response. The VI-RADS scores were dichotomised between 0 and 3 (0 = no evidence of disease) and 4-5. Event-free survival (EFS) and overall survival (OS) analyses were performed. Comprehensive genomic profiling and transcriptome-wide expression profiling data were matched with the VI-RADS scores. RESULTS: In total, 110 patients underwent centrally reviewed scans (N = 220 mpMRI), treated between February 2017 and July 2020. Both pre- and post-pembrolizumab VI-RADS 0-3 scores were the only significant covariates that predicted the ypT≤1N0 endpoint in multivariable analyses, and the strongest effect was seen with post-pembrolizumab VI-RADS 0-3 predicting the ypT≤1N0 response (P < 0.001). The area under the curve for this model was 0.90. Post-pembrolizumab VI-RADS 0-3 also predicted a longer EFS (P < 0.001) and OS (P = 0.044). The scores of several gene signatures from baseline tumours differed between the pre-pembrolizumab VI-RADS 0-3 and 4-5 categories. CONCLUSION: Post-pembrolizumab VI-RADS scores are strongly associated with pathological downstaging and survival. VI-RADS scores were also characterised by distinct biomarker features. These results indicate that the VI-RADS is emerging as an important tool for designing next-generation trials for MIBC.

Comparative Effectiveness of Neoadjuvant Pembrolizumab Versus Cisplatin-based Chemotherapy or Upfront Radical Cystectomy in Patients with Muscle-invasive Urothelial Bladder Cancer.

BACKGROUND: Recent progresses in the use of immune checkpoint inhibitor (ICI) have challenged the therapeutic standards in patients with muscle-invasive urothelial bladder carcinoma (MIBC). OBJECTIVE: To compare neoadjuvant pembrolizumab followed by radical cystectomy (RC) versus neoadjuvant chemotherapy (NAC) and RC or upfront RC, according to cisplatin eligibility. DESIGN, SETTING, AND PARTICIPANTS: We conducted two separate analyses for cisplatin-eligible and cisplatin-ineligible cT2-4N0M0 MIBC patients. We used a propensity score adjustment that relied on inverse probability of treatment-weighting (IPTW). INTERVENTION: Pembrolizumab within the PURE-01 trial, and NAC and RC or upfront RC from a high-volume tertiary care referral center. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint in both analyses was event-free survival (EFS), defined as freedom from recurrence, and/or death from any cause indexed from the date of treatment initiation or RC. The secondary endpoints included EFS in propensity score-matched patients, pathologic response rate, and recurrence-free survival (RFS) after RC. RESULTS AND LIMITATIONS: A total of 458 patients who underwent RC, with or without NAC, at Moffitt Cancer Center between October 2005 and October 2020, and 146 patients enrolled in PURE-01 were analyzed. In cisplatin-ineligible patients, EFS was superior in those receiving pembrolizumab (p < 0.001). The estimated 3-yr EFS was 77.8% (95% confidence interval [CI]: 63.5-95.2) for pembrolizumab and RC, and 36.1% (95% CI: 28.6-45.5) for upfront RC. EFS remained superior in those receiving neoadjuvant ICI (NICI) following IPTW (p < 0.001). In cisplatin-eligible patients, EFS was superior in those receiving pembrolizumab and RC (p < 0.001). The estimated 3-yr EFS was 86.9% (95% CI: 80.9-93.3) for pembrolizumab and 63.5% (95% CI: 56.5-71.4) for NAC. EFS remained superior in those receiving NICI following IPTW (p < 0.001). Pathologic responses and RFS in pembrolizumab-treated patients were also superior to those in NAC-treated patients. Results are limited by the retrospective nature of the study. CONCLUSIONS: In the first ever reported comprehensive comparison of outcomes between neoadjuvant ICI and NAC, followed by RC, or upfront RC, we report increased responses and improved oncologic outcomes with neoadjuvant ICI in patients with MIBC. PATIENT SUMMARY: We compared the results obtained from the use of pembrolizumab and radical cystectomy with standard-of-care treatments in patients with bladder carcinoma infiltrating the muscle layer. We reported increased response and survival rates possibilities with the use of immunotherapy, anticipating the possibility to set new therapeutic standards in these patients, pending the results of ongoing randomized studies.

Genetic Alterations of Melanoma Brain Metastases: A Systematic Review and Meta-Analysis.

BACKGROUND: Data on molecular alterations harbored by melanoma brain metastases (MBMs) are limited, and this has hampered the development of more effective therapeutic strategies. We conducted a systematic review and meta-analysis of all the studies reporting DNA sequencing data of MBMs, in order to identify recurrently mutated genes and molecular pathways significantly enriched for genetic alterations. METHODS: We searched PubMed, Embase and Scopus for articles published from the inception of each database to June 30, 2021. We included in the analysis all the studies that reported individual patient data on DNA sequencing of MBMs, assessing single nucleotide variants (SNVs) and/or gene copy number variations (CNVs) in at least five tumor samples. Meta-analysis was performed for genes evaluated for SNVs and/or CNVs in at least two studies. Pooled proportions of samples with SNVs and/or CNVs was calculated by applying random-effect models based on the DerSimonian-Laird method. Gene-set enrichment analysis (GSEA) was performed to identify molecular pathways significantly enriched for mutated genes. RESULTS: Ten studies fulfilled the inclusion criteria and were included in the analysis, for a total of 531 samples of MBMs evaluated. Twenty-seven genes were found recurrently mutated with a meta-analytic rate of SNVs higher than 5%. GSEA conducted on the list of these 27 recurrently mutated genes revealed vascular endothelial growth factor-activated receptor activity and transmembrane receptor protein tyrosine kinase activity to be among the top 10 gene ontology (GO) molecular functions significantly enriched for mutated genes, while regulation of apoptosis and cell proliferation were among the top 10 significantly enriched GO biological processes. Notably, a high meta-analytic rate of SNVs was found in several actionable cancer-associated genes, such as all the vascular endothelial growth factor (VEGF) receptor isoforms (i.e., Flt1 and Flt2 genes, for both SNV rate: 0.22, 95% CI 0.04-0.49; KDR gene, SNV rate: 0.1, 95% CI 0.05-0.16). Finally, two tumor suppressor genes were characterized by a high meta-analytic rate of CNVs: CDKN2A/B (CNV rate: 0.59, 95% CI 0.23-0.90) and PTEN (CNV rate: 0.31, 95% CI 0.02-0.95). CONCLUSION: MBMs harbored actionable molecular alterations that could be exploited as therapeutic targets to improve the poor prognosis of patients.

Different Response to Immunotherapy According to Melanoma Histologic Subtype.

Superficial spreading melanoma (SSM) and nodular melanoma (NM) are the most common melanoma histologic subtypes and are characterized by different biological features. We retrospectively analyzed all consecutive patients with advanced melanoma, treated with anti-PD-1 and/or anti-CTLA-4 at our center, with data available on primary tumor subtype. The primary objective was to assess the association between histologic subtype and patients' outcomes. In addition, we analyzed whole-exome and whole-transcriptome sequencing data of a cohort of advanced melanoma to identify genes and related pathways, characterized by significant differences between NMs and SSMs. Twenty-one patients with NM and 39 with SSM, treated with anti-PD-1(53/60) as monotherapy or combined with anti-CTLA-4 (7/60), were analyzed. All known clinical-pathologic prognostic factors were well balanced between NM and SSM groups, except for the ECOG-PS score. The overall response rate was 52.4% (95% confidence interval, 29.8-74.3) in the NMs group versus 20.5% (9.3-36.5) in the SSMs group (P-value=0.02). The median progression-free survival and overall survival were, respectively, 13.9 and 44.5 months in the NMs group versus only 3.2 and 12 months in SSMs group (progression-free survival P-value=0.032; overall survival P-value=0.002). Multivariable analysis adjusting for the ECOG-PS, confirmed similar results. Whole-exome and whole-transcriptome data of 28 NMs and 21 SSMs were analyzed. No significant differences were observed in terms of both TMB and frequency of mutation in any gene. A total of 266 genes were overexpressed in NMs as compared with SSMs, and enrichment-analysis revealed a significant enrichment (false discovery rate<0.05) of genes belonging to immune-related pathways involved in antigens presentation mechanisms, response to interferon gamma and neutrophil activation. We provided clinical evidences suggesting a relevant association between melanoma histologic subtype and response to immunotherapy.

Association of Anticancer Immune Checkpoint Inhibitors With Patient-Reported Outcomes Assessed in Randomized Clinical Trials: A Systematic Review and Meta-analysis.

Importance: The association of immune checkpoint inhibitors (ICIs) with patient quality of life has been poorly explored. Objective: To evaluate patient-reported outcomes (PROs) assessed in randomized clinical trials (RCTs) of immunotherapy-based treatments. Data Sources: This systematic review and random-effects meta-analysis used RCTs identified in PubMed, MEDLINE, Embase, and Scopus from database inception to June 1, 2021. Study Selection: A total of 2259 RCTs were identified that assessed ICIs as monotherapy or in combination with chemotherapy or combined with another ICI and/or targeted therapy vs control groups not containing immunotherapy in patients with advanced solid tumors. Studies were reviewed independently by 2 authors. Data Extraction and Synthesis: This meta-analysis followed the PRISMA guidelines and recommendations of the Setting International Standards in Analyzing Patient-Reported Outcomes and Quality of Life Endpoints Data Consortium. Main Outcomes and Measures: The coprimary aims of the meta-analysis were (1) pooled differences between treatment groups in the mean change of PRO score from baseline to 12 and 24 weeks of follow-up and (2) pooled differences between treatment groups in the time to deterioration of PRO score. For each end point, RCTs have been analyzed according to the type of treatment administered in the experimental group: ICIs given as monotherapy, ICIs combined with chemotherapy, or ICIs in association with another ICI and/or with targeted therapies. Results: Of the 2259 identified RCTs, 34 (18 709 patients) met the selection criteria and were analyzed. In the group of 19 RCTs testing ICIs as monotherapy, the pooled between-groups difference of mean change from baseline to 12 weeks of follow-up was 4.6 (95% CI, 2.8-6.4), and the mean change from baseline to 24 weeks of follow-up was 6.1 (95% CI, 4.2-8.1), significantly favoring ICIs. The pooled difference was 1.4 (95% CI, -0.4 to 3.2) at week 12 and 2.5 (95% CI, -0.8 to 5.9) at week 24 in the group of 8 RCTs testing ICIs combined with chemotherapy and 2.1 (95% CI, -0.8 to 5.0) at week 12 and 2.1 (95% CI, -0.4 to 4.5) at week 24 in the group of 8 RCTs testing other ICI-containing combinations. The time to deterioration was significantly longer in the immunotherapy-containing groups compared with control groups in all 3 groups of RCTs evaluated (hazard ratios of 0.80 [95% CI, 0.70-0.91] for ICIs as monotherapy, 0.89 [95% CI, 0.78-1.00] for ICIs plus chemotherapy, and 0.78 [95% CI, 0.63-0.96] for other ICI-containing combinations). Conclusions and Relevance: Immune checkpoint inhibitors as monotherapy appear to have a favorable association with patient-reported quality of life and can be combined with other classes of anticancer drugs without worsening this quality of life.

High Circulating Methylated DNA Is a Negative Predictive and Prognostic Marker in Metastatic Colorectal Cancer Patients Treated With Regorafenib.

Background: Regorafenib improves progression free survival (PFS) in a subset of metastatic colorectal cancer (mCRC) patients, although no biomarkers of efficacy are available. Circulating methylated DNA (cmDNA) assessed by a five-gene panel was previously associated with outcome in chemotherapy treated mCRC patients. We hypothesized that cmDNA could be used to identify cases most likely to benefit from regorafenib (i.e., patients with PFS longer than 4 months). Methods: Plasma samples from mCRC patients were collected prior to (baseline samples N = 60) and/or during regorafenib treatment (N = 62) for the assessment of cmDNA and total amount of cell free DNA (cfDNA). Results: In almost all patients, treatment with regorafenib increased the total cfDNA, but decreased cmDNA warranting the normalization of cmDNA to the total amount of circulating DNA (i.e., cmDNA/ml). We report that cmDNA/ml dynamics reflects clinical response with an increase in cmDNA/ml associated with higher risk of progression (HR for progression = 1.78 [95%CI: 1.01-3.13], p = 0.028). Taken individually, high baseline cmDNA/ml (above median) was associated with worst prognosis (HR for death = 3.471 [95%CI: 1.83-6.57], p < 0.0001) and also predicted shorter PFS (<16 weeks with PPV 86%). In addition, high cmDNA/ml values during regorafenib treatment predicted with higher accuracy shorter PFS (<16 weeks with a PPV of 96%), therefore associated with increased risk of progression (HR for progression = 2.985; [95%CI: 1.63-5.46; p < 0.0001). Conclusions: Our data highlight the predictive and prognostic value of cmDNA/ml in mCRC patients treated with regorafenib.