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3056 Background: An increased number of CH associated mutations has been identified in patients (pts) with solid tumors. Their impact on pts outcomes remains unclear. This study aims to integrate molecular data and clinical characteristics of CH in pts enrolled phase I clinical trials. Methods: Data was collected retrospectively from medical records and molecular profile reports (Foundation One Liquid CDx Assay – 309 genes) performed before first study drug administration at the Drug Development department in Gustave Roussy (Villejuif, France) within the STING trial (NCT04932525). CH prevalence was assessed according to a variant allele frequency (VAF) threshold of 1% in epigenetic modifiers ( DNMT3A, TET2 and ASXL1). Results: From January 2021 to December 2022, 255 pts were enrolled in a phase I clinical trial and had a liquid biopsy. In total, 55% of patients were male with a median age of 62 years [24-86]. Most common tumor locations were gastrointestinal (27%), genitourinary (21%) and thorax (18%). Patients received a median of 2 prior lines of treatment before investigational study drug and CH assessment. At the end of the data cut off, 81% of pts discontinued phase I treatment mostly due to progression disease. Overall, 104 pts (41%) had at least 1 CH mutation in liquid biopsy at baseline with 55 pts (22%) at a VAF of ³ 1%. Mutation frequency was DNMT3A in 42% (n= 23), ASXL1 in 38% (n=21) and TET2 in 31% (n=17). Co-mutations were present in 26 patients, with the most frequent being DNMT3A + ASXL1. Median PFS and OS were 3.7 months (m) for CH group vs 3.5m for no-CH (p=0.3) and 24m CH vs 15m no-CH (p=0.5), respectively. Conclusions: CH is commonly found in pts with solid tumors treated in phase I trials, with a prevalence in our cohort of 22%. Most frequent mutated gene was DNMT3A. Prognostic implications of the impact of these mutations in patient´s outcomes remain to be elucidated and will be presented at the meeting.

Introduction: CHIC (Clonal Hematopoiesis In Lung Cancer) is a retro-prospective study that aims to describe the characteristics of clonal hematopoiesis (CH) in patients with non-small cell lung cancer (NSCLC). We present preliminary results from the retrospective cohort. Experimental procedures: A retrospective analysis conducted in patients with metastatic or recurrent NSCLC included in the MATCH-R study (NCT02517892) at Gustave Roussy (Villejuif, France). CH was evaluated by a 74-gene targeted NGS panel (HaloPlex - Agilent) performed on DNA extracted by isolated-by-blood leukocytes. The variant allele frequency (VAF) threshold of detection was set at 1%. Results: 108 consecutive patients with advanced NSCLC included from October 2015 to July 2019 were evaluated, irrespective of the tumor molecular profile. 46% of the patients were female, 67% were former or current smokers. 82% of the patients had adenocarcinoma and 44%, 23%, 33% had bone, liver and/or brain metastases, respectively. Patients had received a median of 2 lines of systemic therapy and 81% were on active anticancer treatment at the time of CH assessment. At least one CH mutation was found in 38 out of 108 patients (35% prevalence), with an increasing with age trend. Patients carrying CH were older as compared to those without CH and had in 29% vs. 11% of cases tumor histology other than adenocarcinoma (p=0.009). No difference in overall survival was observed according to CH detection (log rank p=0.318). We found 64 mutations in 19 different genes: 63% of the patients carried a single mutation, while co-occurrence of two, three, four or five mutations, within the same gene or in more than one, was found in seven (18%), four (11%), one (3%) and two patients (5%), respectively. Epigenetic modifiers (DNMT3A, TET2, ASXL1) were the most frequently mutated genes: 38 mutations with a median VAF of 6.5% detected in 32 patients. DNA repair genes (PPM1D, TP53, CHEK2, ATM) were the second most frequently mutated: 11 mutations at a median VAF of 4% were detected in 9 patients. 7 mutations in genes encoding for the cohesin complex (SMC3, SMC1A, RAD21, STAG2) were found in 6 patients, with a median VAF of 5%. A non-simultaneous cfDNA sequencing by FoundationOne Liquid CDx assay (324-gene panel) was performed in 9 patients for tumor profiling. In 2 out of 3 tested cases the presence of CH was confirmed in plasma liquid biopsy. 4 patients with no detectable CH by the targeted blood sequencing subsequently were found having CH mutations in plasma NGS, on average 45 months apart. To note, as many as 5 out of the 19 detected mutated genes (PPM1D, SMC3, SMC1A, PRPF8, ZRSR2) are not part of the FDA-approved NGS panel used for cfDNA profiling in solid tumors. Conclusion: We found a consistent prevalence of CH in patients with NSCLC by using a sequencing approach targeted for hematologic disorders. Prognostic implications of CH are under investigation and will be evaluated in the full cohort. Citation Format: Marco Tagliamento, Christophe Marzac, Mihaela Aldea, Damien Vasseur, Arnaud Bayle, Anas Gazzah, Maud Ngocamus, Claudio Nicotra, Julieta Rodriguez, Antonin Levy, Capucine Baldini, Santiago Ponce, Felix Blanc-Durand, Etienne Rouleau, Antoine Italiano, Ludovic Lacroix, Luc Friboulet, David Planchard, Fabrice Barlesi, Yohann Loriot, Jean-Baptiste Micol, Benjamin Besse. Molecular landscape of clonal hematopoiesis in patients with lung cancer: First results of the CHIC study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4526.