Predictors of long-term response to abiraterone in patients with metastastic castration-resistant prostate cancer: a retrospective cohort study

We aimed to identify clinical predictors of long-term response to abiraterone (defined as >12 months drug exposure) in a retrospective cohort of metastatic castration-resistant prostate cancer patients treated in post-docetaxel setting at 24 Italian centers. The Cox proportional hazards model was used to analyze the association between clinical features and the duration of drug exposure. Results were expressed as hazard ratios (HR) with associated 95% confidence intervals (CI). A total of 143 patients met the inclusion criteria. Their median age was 73 years, median Gleason score 8 and median abiraterone exposure 20 months. At the univariate analysis, a significant correlation with the duration of abiraterone exposure was found for Gleason score (HR 0.82, 95% CI 0.71-0.96; p=0.012), PSA (HR 1.10, 95% CI 1.03-1.18; p=0.08) and lactic dehydrogenase levels (HR 1.22, 95% CI 1.02-1.46; p=0.027), while the association between lower alkaline phosphatase levels and treatment duration was marginally significant (HR 1.07, 95% CI 0.99-1.16; p=0.074). Only PSA and Gleason score were predictive of long-term treatment duration in the multivariate analysis. No other clinical factors resulted to be predictive of sustained response to abiraterone, including metastatic disease at diagnosis and visceral disease, suggesting that all subgroups of patients may derive a substantial clinical benefit from abiraterone treatment. These findings need to be validated in prospective, larger studies

Real-world data on cabozantinib in previously treated patients with metastatic renal cell carcinoma: Focus on sequences and prognostic factors

Cabozantinib is approved for the treatment of renal cell carcinoma (RCC). However, prognostic factors are still lacking in this context. The aim of this study was to evaluate prognostic factors in RCC patients treated with second-or third-line cabozantinib. A multicenter retrospective real-world study was conducted, involving 32 worldwide centers. A total of 237 patients with histologically confirmed clear-cell and non-clear-cell RCC who received cabozantinib as second-or third-line therapy for metastatic disease were included. We analyzed overall survival (OS), progression-free survival (PFS) and time-to-strategy failure (TTSF) using Kaplan–Meier curves. Cox proportional models were used at univariate and multivariate analyses.The median PFS and OS of cabozantinib were 7.76 months (95% CI 6.51–10.88) and 11.57 months (95% CI 10.90–not reached (NR)) as second-line and 11.38 months (95% CI 5.79–NR) and NR (95% CI 11.51–NR) as third-line therapy. The median TTSF and OS were 11.57 and 15.52 months with the sequence of cabozantinib–nivolumab and 25.64 months and NR with nivolumab–cabozantinib, respectively. The difference between these two sequences was statistically significant only in good-risk patients. In the second-line setting, hemoglobin (Hb) levels (HR= 2.39; 95% CI 1.24–4.60, p = 0.009) and IMDC (International Metastatic Renal Cell Carcinoma Database Consortium) group (HR = 1.72, 95% CI 1.04–2.87, p = 0.037) were associated with PFS while ECOG-PS (HR = 2.33; 95%CI, 1.16–4.69, p = 0.018) and Hb levels (HR = 3.12; 95%CI 1.18–8.26, p = 0.023) correlated with OS at multivariate analysis, while in the third-line setting, only Hb levels (HR = 2.72; 95%CI 1.04–7.09, p = 0.042) were associated with OS. Results are limited by the retrospective nature of the study.This real-world study provides evidence on the presence of prognostic factors in RCC patients receiving cabozantinib.</p

Validation of a Novel Three-Dimensional (3D Fusion) Gross Sampling Protocol for Clear Cell Renal Cell Carcinoma to Overcome Intratumoral Heterogeneity: The Meet-Uro 18 Study

76siWe aimed to overcome intratumoral heterogeneity in clear cell renal cell carcinoma (clearRCC). One hundred cases of clearRCC were sampled. First, usual standard sampling was applied (1 block/cm of tumor); second, the whole tumor was sampled, and 0.6 mm cores were taken from each block to construct a tissue microarray; third, the residual tissue, mapped by taking pieces 0.5 × 0.5 cm, reconstructed the entire tumor mass. Precisely, six randomly derived pieces of tissues were placed in each cassette, with the number of cassettes being based on the diameter of the tumor (called multisite 3D fusion). Angiogenic and immune markers were tested. Routine 5231 tissue blocks were obtained. Multisite 3D fusion sections showed pattern A, homogeneous high vascular density (10%), pattern B, homogeneous low vascular density (8%) and pattern C, heterogeneous angiogenic signatures (82%). PD-L1 expression was seen as diffuse (7%), low (33%) and absent (60%). Tumor-infiltrating CD8 scored high in 25% (pattern hot), low in 65% (pattern weak) and zero in 10% of cases (pattern desert). Grading was upgraded in 26% of cases (G3-G4), necrosis and sarcomatoid/rhabdoid characters were observed in, respectively, 11 and 7% of cases after 3D fusion (p = 0.03). CD8 and PD-L1 immune expressions were higher in the undifferentiated G4/rhabdoid/sarcomatoid clearRCC subtypes (p = 0.03). Again, 22% of cases were set to intermediate to high risk of clinical recurrence due to new morphological findings of all aggressive G4, sarcomatoid/rhabdoid features by using 3D fusion compared to standard methods (p = 0.04). In conclusion, we propose an easy-to-apply multisite 3D fusion sampling that negates bias due to tumor heterogeneity.noneBrunelli, Matteo; Martignoni, Guido; Malpeli, Giorgio; Volpe, Alessandro; Cima, Luca; Raspollini, Maria Rosaria; Barbareschi, Mattia; Tafuri, Alessandro; Masi, Giulia; Barzon, Luisa; Ammendola, Serena; Villanova, Manuela; Cerruto, Maria Angela; Milella, Michele; Buti, Sebastiano; Bersanelli, Melissa; Fornarini, Giuseppe; Rebuzzi, Sara Elena; Vellone, Valerio Gaetano; Gaggero, Gabriele; Procopio, Giuseppe; Verzoni, Elena; Bracarda, Sergio; Fanelli, Martina; Sabbatini, Roberto; Passalacqua, Rodolfo; Perrucci, Bruno; Giganti, Maria Olga; Donini, Maddalena; Panni, Stefano; Tucci, Marcello; Prati, Veronica; Ortega, Cinzia; Caliò, Anna; Eccher, Albino; Alongi, Filippo; Pappagallo, Giovanni; Iacovelli, Roberto; Mosca, Alessandra; Umari, Paolo; Montagnani, Ilaria; Gobbo, Stefano; Atzori, Francesco; Munari, Enrico; Maruzzo, Marco; Basso, Umberto; Pierconti, Francesco; Patriarca, Carlo; Colombo, Piergiuseppe; Lapini, Alberto; Conti, Giario; Salvioni, Roberto; Bollito, Enrico; Cossarizza, Andrea; Massari, Francesco; Rizzo, Mimma; Franco, Renato; Zito-Marino, Federica; Aberasturi Plata, Yoseba; Galuppini, Francesca; Sbaraglia, Marta; Fassan, Matteo; Dei Tos, Angelo Paolo; Colecchia, Maurizio; Moch, Holger; Scaltriti, Maurizio; Porta, Camillo; Delahunt, Brett; Giannarini, Gianluca; Bortolus, Roberto; Rescigno, Pasquale; Banna, Giuseppe Luigi; Signori, Alessio; Obispo, Miguel Angel Llaja; Perris, Roberto; Antonelli, AlessandroBrunelli, Matteo; Martignoni, Guido; Malpeli, Giorgio; Volpe, Alessandro; Cima, Luca; Raspollini, Maria Rosaria; Barbareschi, Mattia; Tafuri, Alessandro; Masi, Giulia; Barzon, Luisa; Ammendola, Serena; Villanova, Manuela; Cerruto, Maria Angela; Milella, Michele; Buti, Sebastiano; Bersanelli, Melissa; Fornarini, Giuseppe; Rebuzzi, Sara Elena; Vellone, Valerio Gaetano; Gaggero, Gabriele; Procopio, Giuseppe; Verzoni, Elena; Bracarda, Sergio; Fanelli, Martina; Sabbatini, Roberto; Passalacqua, Rodolfo; Perrucci, Bruno; Giganti, Maria Olga; Donini, Maddalena; Panni, Stefano; Tucci, Marcello; Prati, Veronica; Ortega, Cinzia; Caliò, Anna; Eccher, Albino; Alongi, Filippo; Pappagallo, Giovanni; Iacovelli, Roberto; Mosca, Alessandra; Umari, Paolo; Montagnani, Ilaria; Gobbo, Stefano; Atzori, Francesco; Munari, Enrico; Maruzzo, Marco; Basso, Umberto; Pierconti, Francesco; Patriarca, Carlo; Colombo, Piergiuseppe; Lapini, Alberto; Conti, Giario; Salvioni, Roberto; Bollito, Enrico; Cossarizza, Andrea; Massari, Francesco; Rizzo, Mimma; Franco, Renato; Zito-Marino, Federica; Aberasturi Plata, Yoseba; Galuppini, Francesca; Sbaraglia, Marta; Fassan, Matteo; Dei Tos, Angelo Paolo; Colecchia, Maurizio; Moch, Holger; Scaltriti, Maurizio; Porta, Camillo; Delahunt, Brett; Giannarini, Gianluca; Bortolus, Roberto; Rescigno, Pasquale; Banna, Giuseppe Luigi; Signori, Alessio; Obispo, Miguel Angel Llaja; Perris, Roberto; Antonelli, Alessandr

Validation of a Novel Three-Dimensional (3D Fusion) Gross Sampling Protocol for Clear Cell Renal Cell Carcinoma to Overcome Intratumoral Heterogeneity: The Meet-Uro 18 Study

We aimed to overcome intratumoral heterogeneity in clear cell renal cell carcinoma (clearRCC). One hundred cases of clearRCC were sampled. First, usual standard sampling was applied (1 block/cm of tumor); second, the whole tumor was sampled, and 0.6 mm cores were taken from each block to construct a tissue microarray; third, the residual tissue, mapped by taking pieces 0.5 × 0.5 cm, reconstructed the entire tumor mass. Precisely, six randomly derived pieces of tissues were placed in each cassette, with the number of cassettes being based on the diameter of the tumor (called multisite 3D fusion). Angiogenic and immune markers were tested. Routine 5231 tissue blocks were obtained. Multisite 3D fusion sections showed pattern A, homogeneous high vascular density (10%), pattern B, homogeneous low vascular density (8%) and pattern C, heterogeneous angiogenic signatures (82%). PD-L1 expression was seen as diffuse (7%), low (33%) and absent (60%). Tumor-infiltrating CD8 scored high in 25% (pattern hot), low in 65% (pattern weak) and zero in 10% of cases (pattern desert). Grading was upgraded in 26% of cases (G3-G4), necrosis and sarcomatoid/rhabdoid characters were observed in, respectively, 11 and 7% of cases after 3D fusion (p = 0.03). CD8 and PD-L1 immune expressions were higher in the undifferentiated G4/rhabdoid/sarcomatoid clearRCC subtypes (p = 0.03). Again, 22% of cases were set to intermediate to high risk of clinical recurrence due to new morphological findings of all aggressive G4, sarcomatoid/rhabdoid features by using 3D fusion compared to standard methods (p = 0.04). In conclusion, we propose an easy-to-apply multisite 3D fusion sampling that negates bias due to tumor heterogeneity

Significance of PD-L1 in Metastatic Urothelial Carcinoma Treated With Immune Checkpoint Inhibitors

Importance Immune checkpoint inhibitors (ICIs) have broadened the metastatic urothelial carcinoma (mUC) therapeutic scenario. The association of programmed death ligand 1 (PD-L1) with response and survival in patients treated with ICIs is still controversial. Objectives To evaluate the association of PD-L1 with response rate and overall survival among patients with mUC treated with ICIs. Data Sources PubMed, Embase, American Society of Clinical Oncology and European Society for Medical Oncology Meeting Libraries, and Web of Science were searched up to December 10, 2023. Study Selection Two authors independently screened the studies. Included studies were randomized and nonrandomized clinical trials enrolling patients with mUC receiving ICIs with available overall survival (OS), progression-free survival (PFS), or overall response rate (ORR) data, separated between patients with PD-L1-positive and -negative tumors. Data Extraction and Synthesis The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Two reviewers independently extracted data. Fixed- or random-effects models were used depending on the heterogeneity among the studies. Main Outcomes and Measures Primary outcomes were odds ratios (ORs) for ORR and hazard ratios (HRs) for OS, comparing patients with PD-L1-positive tumors and patients with PD-L1-negative tumors. Secondary outcomes were the PFS HR between patients with PD-L1-positive and -negative tumors and OS HR between ICI arms and non-ICI arms of only randomized clinical trials. Results A total of 14 studies were selected, comprising 5271 patients treated with ICIs (2625 patients had PD-L1-positive tumors). The ORR was 13.8% to 78.6% in patients with PD-L1-positive tumors and 5.1% to 63.2% in patients with PD-L1-negative tumors, with an association between PD-L1 status and ORR favoring patients with PD-L1-positive tumors (OR, 1.94; 95% CI, 1.47-2.56; P < .001). Median OS ranged from 8.4 to 24.1 months in patients with PD-L1-positive tumors and from 6.0 to 19.1 months in patients with PD-L1-negative tumors. The pooled HR showed a significant reduction for patients with PD-L1-positive tumors compared with those with PD-L1-negative tumors in the risk of death (HR, 0.71; 95% CI, 0.57-0.89; P = .003) and risk of progression (HR, 0.55; 95% CI, 0.44-0.69; P < .001) when ICIs were administered. PD-L1 is not likely to be a predictive biomarker of ICI response. Conclusions and Relevance This systematic review and meta-analysis suggests that PD-L1 expression is associated with improved ORR, OS, and PFS for patients with mUC who receive ICIs, but it is unlikely to be useful as a predictive biomarker. Developing predictive biomarkers is essential to select patients most likely to benefit from ICIs and avoid toxic effects and financial burden with these agents