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4 results on '"Neoadjuvant pembrolizumab"'

1. Can Patients with Muscle-invasive Bladder Cancer and Fibroblast Growth Factor Receptor-3 Alterations Still Be Considered for Neoadjuvant Pembrolizumab? A Comprehensive Assessment from the Updated Results of the PURE-01 Study

Author

Jeffrey S. Ross, Filippo Pederzoli, Andrea Salonia, Ewan A. Gibb, Ryan Dittamore, Maurizio Colecchia, Joep J. de Jong, Giorgio Gandaglia, Nicola Fossati, Marco Bandini, Patrizia Giannatempo, Roberta Lucianò, Laura Marandino, Andrea Gallina, Daniele Raggi, Yang Liu, Alberto Briganti, Elai Davicioni, Andrea Necchi, Francesco Montorsi, Elena Farè, Urology, Necchi, Andrea, Raggi, Daniele, Giannatempo, Patrizia, Marandino, Laura, Farè, Elena, Gallina, Andrea, Colecchia, Maurizio, Lucianò, Roberta, Salonia, Andrea, Gandaglia, Giorgio, Fossati, Nicola, Bandini, Marco, Pederzoli, Filippo, Dittamore, Ryan, Liu, Yang, Davicioni, Elai, Ross, Jeffrey S, de Jong, Joep J, Briganti, Alberto, Montorsi, Francesco, and Gibb, Ewan A

Subjects
musculoskeletal diseases, Oncology, congenital, hereditary, and neonatal diseases and abnormalities, medicine.medical_specialty, Urology, medicine.medical_treatment, 030232 urology & nephrology, Pembrolizumab, Antibodies, Monoclonal, Humanized, Cystectomy, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, SDG 3 - Good Health and Well-being, Internal medicine, medicine, Clinical endpoint, Humans, Hedgehog Proteins, Radiology, Nuclear Medicine and imaging, Fibroblast growth factor receptor-3 activity, Fibroblast growth factor receptor-3 mutations/fusions, Bladder cancer, business.industry, Muscles, Immunotherapy, Fibroblast growth factor receptor 3, Neoadjuvant pembrolizumab, musculoskeletal system, medicine.disease, Neoadjuvant Therapy, Fibroblast growth factor receptor-3 expression, Gene expression profiling, stomatognathic diseases, Exact test, Urinary Bladder Neoplasms, 030220 oncology & carcinogenesis, Surgery, business, Muscle-invasive bladder cancer
Abstract

In the PURE-01 study, patients with muscle-invasive bladder cancer (MIBC) who achieved a pathological complete response (CR; ypT0N0) had tumor features suggesting that pre-existing immunity may promote response. We focused on fibroblast growth factor receptor-3 (FGFR3) genomic alterations (GAs) as potential tumor resistance features. The primary endpoint of our study was CR. FGFR3 GAs were assessed via comprehensive genomic profiling of sequenced DNA (N = 112), a transcriptome-based FGFR3 activity signature, an FGFR3 subtyping model based on long noncoding RNA (lncRNA), and gene expression profiling (N = 84 for all three). We used Wilcoxon rank-sum tests, Fisher's exact test, and logistic regression analyses to analyze the associations between the various FGFR3 alterations and CR. High FGFR3 activity was defined as a signature score that was higher than the median value. Cases that were positive for lncRNA-FGFR3 subtype (lncRNA-FGFR3 active, N = 11) had consistent biology with published data: low epithelial-mesenchymal transition and immune-signature scores, high p53 activity, FGFR3 activity, and sonic hedgehog activity. In total, 17 (15.2%), 42 (50%), and 11 patients (13%) showed FGFR3 GAs or high FGFR3 signature scores, or had lncRNA-FGFR3–active tumors. Despite an association of high FGFR3 gene expression with a lower CR rate (p = 0.01), we did not find a correlation between FGFR3 activity or mutation/fusion and CR (p = 0.2 and p = 0.8). We conclude that the association of FGFR3 expression with pathological response is balanced by multiple factors. Overall, FGFR3-altered tumors should not be excluded from neoadjuvant immunotherapy studies at this time. Patient summary In patients with muscle-invasive bladder cancer treated within the PURE-01 trial, we analyzed the role of fibroblast growth factor receptor-3 (FGFR3) alterations, at the DNA and RNA levels, in association with the pathological response. We did not find any robust association, mainly when analyzing the landscape of alterations defining tumors with higher biological FGFR activity. Overall, FGFR3 activity and gene alterations did not provide sufficiently robust data to exclude patients whose tumors harbor these alterations from neoadjuvant immunotherapy trials.

Published
2021

2. Molecular subtyping and immune-gene signatures identify a subset of early bladder tumors as candidates for single-agent immune-checkpoint inhibition

Author

Daniele Raggi, Ewan A. Gibb, Andrea Necchi, Andrea Gallina, Yair Lotan, Marco Bandini, Francesco Montorsi, Laura Marandino, Joep J. de Jong, Elai Davicioni, Alberto Briganti, Necchi, A., Raggi, D., Gallina, A., Bandini, M., de Jong, J. J., Marandino, L., Briganti, A., Montorsi, F., Davicioni, E., Lotan, Y., and Gibb, E. A.

Subjects
Male, Oncology, medicine.medical_specialty, Urology, medicine.medical_treatment, Population, Cystectomy, Internal medicine, Humans, Medicine, education, Immune Checkpoint Inhibitors, Neoadjuvant therapy, Aged, education.field_of_study, Bladder cancer, business.industry, Gene Expression Profiling, Tumor biomarkers, Immunotherapy, Middle Aged, Neoadjuvant pembrolizumab, medicine.disease, Immune checkpoint, Radical cystectomy, Treatment Outcome, Urinary Bladder Neoplasms, Specimen collection, Cohort, Female, business, Muscle-invasive bladder cancer
Abstract

Purpose Clinical high-grade (HG) T1 non-muscle invasive bladder cancer (NMIBC) represents a significant risk to patients, but these patients are not typically offered neoadjuvant therapies, including immune therapy. In this study, we determine whether patients with HG clinical T1 or T2 bladder urothelial carcinoma (UC) have profiles that predict the potential effectiveness of immune-checkpoint inhibitors (ICI). Materials and Methods Data from transurethral resection of bladder tumor (TURBT) specimens from 2 studies was evaluated. The molecular upstaging (MOL) cohort included HG cT1N0M0 (n = 87) and cT2N0M0 (n = 119) bladder UC who underwent radical cystectomy (RC) without any neoadjuvant therapy. The PURE-01 cohort (n = 102) was used as ICI-treated reference. Specimen collection and sample processing were conducted using a clinical-grade whole-transcriptome assay (Decipher). Immune-signatures scores and molecular subtyping were evaluated. Kaplan-Meier curves and log-rank tests were used for exploratory analyses of recurrence-free survival (RFS) and overall survival (OS). Results In both the PURE-01 and MOL cohorts, the Immune190 signature, stratified by subtype, showed the highest scores in basal-type, but also in luminal-infiltrated tumors, but the lowest scores in the luminal tumors. However, in HG cT1 tumors the Immune190 scores were the lowest for luminal papillary tumors (Consensus, TCGA) and luminal tumors (GSC), with less distinct differences between other subtypes. RFS was significantly longer for luminal vs non-luminal tumors in MOL (P = 0.04) but not in PURE-01 (P = 0.8). In the MOL cohort, OS was inferior in HG cT1 tumors for Immune190-high vs low tumors (median split, P = 0.042). Conclusion We identified a population of cT1-T2N0M0 tumors in the MOL cohort that shared molecular features with tumors included in PURE-01. These profiles suggest that treatment with ICI could be proposed to more selected HG cT1N0M0 tumors, identified with a gene expression assay.

Published
2021

3. Molecular subtyping and immune-gene signatures identify a subset of early bladder tumors as candidates for single-agent immune-checkpoint inhibition.

Author

Necchi, Andrea, Raggi, Daniele, Gallina, Andrea, Bandini, Marco, de Jong, Joep J., Marandino, Laura, Briganti, Alberto, Montorsi, Francesco, Davicioni, Elai, Lotan, Yair, and Gibb, Ewan A.

Subjects
*IMMUNE checkpoint inhibitors, *BLADDER cancer, *OVERALL survival, *CANCER invasiveness, *TRANSITIONAL cell carcinoma, TUMOR surgery
Abstract

Purpose: Clinical high-grade (HG) T1 non-muscle invasive bladder cancer (NMIBC) represents a significant risk to patients, but these patients are not typically offered neoadjuvant therapies, including immune therapy. In this study, we determine whether patients with HG clinical T1 or T2 bladder urothelial carcinoma (UC) have profiles that predict the potential effectiveness of immune-checkpoint inhibitors (ICI).Materials and Methods: Data from transurethral resection of bladder tumor (TURBT) specimens from 2 studies was evaluated. The molecular upstaging (MOL) cohort included HG cT1N0M0 (n = 87) and cT2N0M0 (n = 119) bladder UC who underwent radical cystectomy (RC) without any neoadjuvant therapy. The PURE-01 cohort (n = 102) was used as ICI-treated reference. Specimen collection and sample processing were conducted using a clinical-grade whole-transcriptome assay (Decipher). Immune-signatures scores and molecular subtyping were evaluated. Kaplan-Meier curves and log-rank tests were used for exploratory analyses of recurrence-free survival (RFS) and overall survival (OS).Results: In both the PURE-01 and MOL cohorts, the Immune190 signature, stratified by subtype, showed the highest scores in basal-type, but also in luminal-infiltrated tumors, but the lowest scores in the luminal tumors. However, in HG cT1 tumors the Immune190 scores were the lowest for luminal papillary tumors (Consensus, TCGA) and luminal tumors (GSC), with less distinct differences between other subtypes. RFS was significantly longer for luminal vs non-luminal tumors in MOL (P = 0.04) but not in PURE-01 (P = 0.8). In the MOL cohort, OS was inferior in HG cT1 tumors for Immune190-high vs low tumors (median split, P = 0.042).Conclusion: We identified a population of cT1-T2N0M0 tumors in the MOL cohort that shared molecular features with tumors included in PURE-01. These profiles suggest that treatment with ICI could be proposed to more selected HG cT1N0M0 tumors, identified with a gene expression assay. [ABSTRACT FROM AUTHOR]

Published
2021
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4. Can Patients with Muscle-invasive Bladder Cancer and Fibroblast Growth Factor Receptor-3 Alterations Still Be Considered for Neoadjuvant Pembrolizumab? A Comprehensive Assessment from the Updated Results of the PURE-01 Study.

Author

Necchi A, Raggi D, Giannatempo P, Marandino L, Farè E, Gallina A, Colecchia M, Lucianò R, Salonia A, Gandaglia G, Fossati N, Bandini M, Pederzoli F, Dittamore R, Liu Y, Davicioni E, Ross JS, de Jong JJ, Briganti A, Montorsi F, and Gibb EA

Subjects
Antibodies, Monoclonal, Humanized, Cystectomy, Hedgehog Proteins, Humans, Muscles, Neoadjuvant Therapy, Urinary Bladder Neoplasms drug therapy, Urinary Bladder Neoplasms genetics, Urinary Bladder Neoplasms surgery
Abstract

In the PURE-01 study, patients with muscle-invasive bladder cancer (MIBC) who achieved a pathological complete response (CR; ypT0N0) had tumor features suggesting that pre-existing immunity may promote response. We focused on fibroblast growth factor receptor-3 (FGFR3) genomic alterations (GAs) as potential tumor resistance features. The primary endpoint of our study was CR. FGFR3 GAs were assessed via comprehensive genomic profiling of sequenced DNA (N = 112), a transcriptome-based FGFR3 activity signature, an FGFR3 subtyping model based on long noncoding RNA (lncRNA), and gene expression profiling (N = 84 for all three). We used Wilcoxon rank-sum tests, Fisher's exact test, and logistic regression analyses to analyze the associations between the various FGFR3 alterations and CR. High FGFR3 activity was defined as a signature score that was higher than the median value. Cases that were positive for lncRNA-FGFR3 subtype (lncRNA-FGFR3 active, N = 11) had consistent biology with published data: low epithelial-mesenchymal transition and immune-signature scores, high p53 activity, FGFR3 activity, and sonic hedgehog activity. In total, 17 (15.2%), 42 (50%), and 11 patients (13%) showed FGFR3 GAs or high FGFR3 signature scores, or had lncRNA-FGFR3-active tumors. Despite an association of high FGFR3 gene expression with a lower CR rate (p = 0.01), we did not find a correlation between FGFR3 activity or mutation/fusion and CR (p = 0.2 and p = 0.8). We conclude that the association of FGFR3 expression with pathological response is balanced by multiple factors. Overall, FGFR3-altered tumors should not be excluded from neoadjuvant immunotherapy studies at this time. PATIENT SUMMARY: In patients with muscle-invasive bladder cancer treated within the PURE-01 trial, we analyzed the role of fibroblast growth factor receptor-3 (FGFR3) alterations, at the DNA and RNA levels, in association with the pathological response. We did not find any robust association, mainly when analyzing the landscape of alterations defining tumors with higher biological FGFR activity. Overall, FGFR3 activity and gene alterations did not provide sufficiently robust data to exclude patients whose tumors harbor these alterations from neoadjuvant immunotherapy trials., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Published
2021
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