Extensive molecular profiling of squamous cell anal carcinoma in a phase 2 trial population: Translational analyses of the "CARACAS" study

Alessandra A Prete; Paolo Manca; Marco Messina; Vincenzo Formica; Giovanni L Frassineti; Maria G Zampino; Domenico C Corsi; Corrado Orciuolo; Michele Prisciandaro; Francesca Bergamo; Valentina Angerilli; Mario Scartozzi; Mariaelena Casagrande; Gianluca Masi; Monica Ronzoni; Federica Morano; Valentina Vettore; Roberta Salmaso; Cosimo Rasola; Giulia Maddalena; Paola Del Bianco; Massimo Milione; Chiara Cremolini; Matteo Fassan; Filippo Pietrantonio; Sara Lonardi

doi: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

Eur J Cancer. 2023 Mar:182:87-97. doi: 10.1016/j.ejca.2022.12.025. Epub 2023 Jan 9.

Authors

Alessandra A Prete¹, Paolo Manca², Marco Messina³, Vincenzo Formica⁴, Giovanni L Frassineti⁵, Maria G Zampino⁶, Domenico C Corsi⁷, Corrado Orciuolo⁸, Michele Prisciandaro², Francesca Bergamo¹, Valentina Angerilli⁹, Mario Scartozzi¹⁰, Mariaelena Casagrande¹¹, Gianluca Masi¹², Monica Ronzoni¹³, Federica Morano², Valentina Vettore¹, Roberta Salmaso⁹, Cosimo Rasola¹⁴, Giulia Maddalena¹⁴, Paola Del Bianco¹⁵, Massimo Milione¹⁶, Chiara Cremolini¹⁷, Matteo Fassan¹⁸, Filippo Pietrantonio², Sara Lonardi¹

Affiliations

¹ Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
² Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumouri, Milan, Italy.
³ Oncologia, Fondazione Istituto G. Giglio, Cefalù, Italy.
⁴ Medical Oncology Unit, Policlinico Tor Vergata, Rome, Italy.
⁵ Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumouri "Dino Amadori" (IRST), Meldola, Italy.
⁶ Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumours, European Institute of Oncology - IRCCS, Milan, Italy.
⁷ Medical Oncology Unit Ospedale San Giovanni Calibita Fatebenefratelli, Rome, Italy.
⁸ Oncology Unit, Department of Radiology, Oncology and Human Pathology, Sapienza University of Rome, Italy.
⁹ Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua Padua, Italy.
¹⁰ Medical Oncology Department, University of Cagliari, Italy.
¹¹ Department of Oncology, Azienda Sanitaria Universitaria Integrata di Udine, Italy.
¹² Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy.
¹³ Oncologia Medica, IRCCS Ospedale San Raffaele, Milan, Italy.
¹⁴ Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy; Department of Surgery, Oncology and Gastroenterology, University of Padua, 35128 Padua, Italy.
¹⁵ Clinical Research Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
¹⁶ Department of the Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumouri, Milan, Italy.
¹⁷ Unit of Medical Oncology 2, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy; Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Italy. Electronic address: [email protected].
¹⁸ Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit, University of Padua Padua, Italy; Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.

PMID: 36753836
DOI: 10.1016/j.ejca.2022.12.025

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 characterised 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.

Keywords: Anti-EGFR; Anti-PD-L1; Immunotherapy; Squamous cell anal carcinoma; Tumour mutation burden.

Publication types

Clinical Trial, Phase II
Research Support, Non-U.S. Gov't

MeSH terms

B7-H1 Antigen
Carcinoma, Squamous Cell*
Epithelial Cells / chemistry
Epithelial Cells / metabolism
Epithelial Cells / pathology
Humans
Immune Checkpoint Inhibitors / therapeutic use
Lung Neoplasms* / drug therapy
Prognosis

Substances

B7-H1 Antigen
Immune Checkpoint Inhibitors

Associated data

ClinicalTrials.gov/NCT03944252