background: molecular characteristics of squamous cell anal carcinoma (SCAC) are poorly explored. Immune checkpoint inhibitors showed limited activity in phase I/II trials, but predictive and prognostic biomarkers are lacking.patients and methods: In the phase II randomised trial CARACAS (NCT03944252), avelumab alone (Arm A) or with cetuximab (Arm B) was tested in pre-treated advanced SCAC , with overall response rate being the primary end-point. on pre-treatment tumour tissue samples, we assessed human papillomavirus status, programmed-death ligand 1 (PD-L1) expression, mismatch repair proteins expression, tumour mutational burden (TMB) and comprehensive genomic profiling by foundationone CDx. tumour-infiltrating lymphocytes were charac-terised on haematoxylin-eosine-stained samples. primary objective was to describe response to immunotherapy in the CARACAS trial population according to molecular and histological characteristics. secondary objectives were to assess progression-free survival (PFS) and overall survival (OS) according to molecular biomarkers.results: high PD-L1 (>40 with combined positive score) was significantly more frequent in patients with disease control (p = 0.0109). High TMB (>10 mutations per megabase) was related to better OS (hazard ratio (HR) = 0.09; 95%confidence interval (CI) 0.01-0.68 ; p = 0.019) and PFS (HR = 0.44; 95% CI = 0.15-1.27 ; p = 0.129). high expression of PD-L1 conferred longer OS (HR = 0.46; 95%CI = 0.19-1.08; p = 0.075) and PFS (HR = 0.42; 95%CI = 0.20-0.92; p = 0.03). neither OS (HR = 1.30; 95%CI = 0.72-2.36; p = 0.39) or PFS (HR = 1.31; 95%CI = 0.74-2.31; p = 0.357) was affected by high (>1.2) tumour-infiltrating lymphocytes count. high TMB and PD-L1identified patients were with significantly better OS (HR = 0.33; 95%CI = 0.13-0.81 ; p = 0.015) and PFS (HR = 0.48; 95%CI = 0.23-1.00; p = 0.015). conclusions: To our knowledge, translaCARACAS is the first study to document prognostic role of TMB and PD-L1 in advanced SCAC patients treated with immune checkpoint inhibitors. 2023 the authors. published by elsevier Ltd. this is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Prete, A.a., Manca, P., Messina, M., Formica, V., Frassineti, G.l., Zampino, M.g., et al. (2023). Extensive molecular profiling of squamous cell anal carcinoma in a phase 2 trial population: Translational analyses of the ?CARACAS? study. EUROPEAN JOURNAL OF CANCER, 182, 87-97 [10.1016/j.ejca.2022.12.025].
Extensive molecular profiling of squamous cell anal carcinoma in a phase 2 trial population: Translational analyses of the ?CARACAS? study
Formica, V.Data Curation
;
2023-01-01
Abstract
background: molecular characteristics of squamous cell anal carcinoma (SCAC) are poorly explored. Immune checkpoint inhibitors showed limited activity in phase I/II trials, but predictive and prognostic biomarkers are lacking.patients and methods: In the phase II randomised trial CARACAS (NCT03944252), avelumab alone (Arm A) or with cetuximab (Arm B) was tested in pre-treated advanced SCAC , with overall response rate being the primary end-point. on pre-treatment tumour tissue samples, we assessed human papillomavirus status, programmed-death ligand 1 (PD-L1) expression, mismatch repair proteins expression, tumour mutational burden (TMB) and comprehensive genomic profiling by foundationone CDx. tumour-infiltrating lymphocytes were charac-terised on haematoxylin-eosine-stained samples. primary objective was to describe response to immunotherapy in the CARACAS trial population according to molecular and histological characteristics. secondary objectives were to assess progression-free survival (PFS) and overall survival (OS) according to molecular biomarkers.results: high PD-L1 (>40 with combined positive score) was significantly more frequent in patients with disease control (p = 0.0109). High TMB (>10 mutations per megabase) was related to better OS (hazard ratio (HR) = 0.09; 95%confidence interval (CI) 0.01-0.68 ; p = 0.019) and PFS (HR = 0.44; 95% CI = 0.15-1.27 ; p = 0.129). high expression of PD-L1 conferred longer OS (HR = 0.46; 95%CI = 0.19-1.08; p = 0.075) and PFS (HR = 0.42; 95%CI = 0.20-0.92; p = 0.03). neither OS (HR = 1.30; 95%CI = 0.72-2.36; p = 0.39) or PFS (HR = 1.31; 95%CI = 0.74-2.31; p = 0.357) was affected by high (>1.2) tumour-infiltrating lymphocytes count. high TMB and PD-L1identified patients were with significantly better OS (HR = 0.33; 95%CI = 0.13-0.81 ; p = 0.015) and PFS (HR = 0.48; 95%CI = 0.23-1.00; p = 0.015). conclusions: To our knowledge, translaCARACAS is the first study to document prognostic role of TMB and PD-L1 in advanced SCAC patients treated with immune checkpoint inhibitors. 2023 the authors. published by elsevier Ltd. this is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
