Abstract C068: Factors associated with primary resistance to immune checkpoint blockade in early phase clinical trials
Authors: Champiat Stéphane , Matte Paul , Baldini Capucine , Vasseur Damien , Ouali Kaïssa , Gazzah Anas , Bahleda Rastilav , Bayle Arnaud , Postel-Vinay Sophie , Smolenschi Cristina , Sakkal Madona , Michot Jean-Marie , Hollebecque Antoine , Chaput-Gras Nathalie , Loriot Yohann , Ponce Santiago , Italiano Antoine , Marabelle Aurélien , Danlos François-Xavier 
Published: December 2023

Abstract
Introduction: Immune checkpoint blockade (ICB) therapies, particularly anti-PD1/PD-L1 monoclonal antibodies, have transformed the field of medical oncology. However, many patients with advanced cancer demonstrate primary resistance to ICB strategies. The identification of objective clinical and biological characteristics associated with treatment resistance is crucial for identifying patients who are most likely not to benefit from conventional or current ICB combinations strategies. Studies and trials dedicated to these patients are essential to overcome such resistance.
Methods: We prospectively enrolled patients treated with ICB at Gustave Roussy between 2018 and 2022 in the PREMIS study (NCT03984318). We examined a sub-cohort of patients treated at the early drug development department (DITEP). We identified pre-treatment (baseline) clinical and biological characteristics, including patients’ oncogenic alterations documented via circulating tumor DNA (ctDNA) sequencing in our STING study (NCT04932525), to find a significant difference between patients according to their best objective antitumor response (BOR; complete response [CR], partial response [PR], stable disease [SD], or progressive disease [PD]).
Results: We analyzed a total of 227 patients, with paired ctDNA available for 96 patients. Patients were 52% women and 48% men, averaging 59 years old, with 24 different solid tumor types and enrolled in 50 different early phase clinical trials. Eleven percent of patients had received prior ICB treatment. BOR were PD (61%), SD (20%), PR (15%), and CR (4%). We identified clinical characteristics significantly different between patients according to their BOR: performance status (PS), number of previous lines of therapy, number of metastases, presence of liver metastases, absolute neutrophils count (ANC), absolute lymphocyte count (ALC), neutrophil to lymphocyte ratio, CRP, GGT and LDH plasma concentrations, and MLH1 mutations. Acording these results, a score from 0 to 5 was calculated according to the presence of the following characteristics (yes=+1): presence of liver metastases, ALC below the lower limit of the normal (LLN), ANC above the upper limit of the normal (ULN), CRP &gt; ULN, LDH &gt; ULN. Patients with a score ≥ 4 did not develop a response during ICB treatments (n=27, 12%). Among them, 25 (92.6%) had a PS of 0-1 and 9 (33.3%) had a Royal Marsden Hospital (RMH) score of 1. Additionally, both progression-free survival (PFS) and overall survival (OS) decreased significantly with the addition of each point score.
Conclusion: Patients with advanced cancer treated by ICB in early phase clinical trials with at least 4 detrimental characteristics (presence of liver metastases, ALC &lt; LLN, ANC, CRP and LDH &gt; ULN) had primary resistance to ICB regardless of tumor type, ICB regimen, PS or RMH. Identification of immunological and oncogenic alterations specific to these patients could support the development of targeted and personalized ICB combination trials to overcome tumor resistance.
Citation Format: Stéphane Champiat, Paul Matte, Capucine Baldini, Damien Vasseur, Kaïssa Ouali, Anas Gazzah, Rastilav Bahleda, Arnaud Bayle, Sophie Postel-Vinay, Cristina Smolenschi, Madona Sakkal, Jean-Marie Michot, Antoine Hollebecque, Nathalie Chaput-Gras, Yohann Loriot, Santiago Ponce, Antoine Italiano, Aurélien Marabelle, François-Xavier Danlos. Factors associated with primary resistance to immune checkpoint blockade in early phase clinical trials [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C068.