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Background: Breast cancer (BC) is the most frequent cancer and the second leading cause of cancer death for women. Although there is a need of new treatments to improve BC outcome, patients with BC are still under-represented in early phase trials, possibly because of the availability of numerous approved treatments and widely recruiting phase II and III trials. We aim to characterize the molecular profile, outcome and prognostic factors of patients with BC treated in a phase I trial at our institution. Methods: We retrospectively analyzed medical records of every BC patients treated consecutively in a phase I trial in the Early Drug Development Department (DITEP) at Gustave Roussy Cancer Center. Multivariate logistic regression models were used to determine the association between known prognostic factors such as ECOG, LDH or albumin levels, number of previous lines of treatment, metastatic sites and duration of treatment. When available, molecular profile was also reviewed. Results: Between April 1st 2008 and December 31th 2021, 4682 patients were enrolled and treated in a phase I trial in our department. Among them, 272 were treated for BC (5.8%): 271 women and 1 man, in 74 different trials. The median number of BC patients treated per year was 16.5 (min 1; max 33). Median time between consented date and C1D1 was 14 days (min 1; max 63). Median age at C1D1 was 50 years old (min 24; max 82). 5 patients (1.8%) were treated in an adjuvant setting (therapeutic vaccine) while all the others were metastatic. 12 patients (4.5%) had brain metastases and 127 patients (47.6%) had liver metastases. 186 patients (70%) had only 1 or 2 metastatic sites, and 81 (30%) had three or more sites. Triple negative was the most common subtype, representing 132 patients (48.5%), 125 (46%) were ER+ and 15 (5.5%) Her2+. Patients received a median number of 3 prior lines before enrollment (min 0; max 19). Overall, only 78 patients (28%) had a genetic testing: 30.7% had a germline BRCA1/2 mutation. 146 patients (54%) had a molecular profile (liquid biopsy or tissue sample) before their enrollment and among them 32,9% were oriented in a trial according to their specific profile. Regarding the type of treatments received: 21.7% were immunotherapy, 73.6% were targeted therapies (46.7% in monotherapy, 26.9% in different combinations with immunotherapy, chemotherapy, radiotherapy or endocrine treatments), 2.9% were chemotherapy and 1.8% endocrine therapy. The overall response rate was 11.1% (0.4% complete response, 10.7% partial response, 37.5% stable disease, 43.8% progressive disease and 7.6% not evaluable). Main reasons for discontinuation of treatment were: progressive disease (80.5%), toxicity (9.6%) and end of trial (6.6%). Median duration of treatment was 2 months (min 0; max 44), only 28.6% of patients were still treated after 3 months of trial and 10% at 6 months. At data cut off (June 21st 2022) median overall survival was 11 months. All patients had discontinued the trial by the time of the analysis: median number of lines of subsequent treatment was 2 (min 0; max 10) and 31 patients (11%) were enrolled in another phase I trial in our center. In a multivariate analysis, there was no prognostic factor associated with duration of treatment whether it was albumin (p=0.76) or LDH levels (p=0.68), ECOG (p=0.67), number of prior lines of treatment (p=0.79) or number of metastatic site (p=0.05). Conclusion: These results are consistent with prior published data as only few patients with BC are addressed for inclusion in a phase I trial, despite response rates and survival rates similar to other phase I patients. We did not find any specific factor associated with duration of treatment. It is likely that a thorough molecular profile could open more treatment options and access to phase I trials. Citation Format: Lauren Seknazi, Arthur Geraud, Vincent Goldschmidt, Capucine Baldini, Stéphane Champiat, Christophe Massard, Sophie Postel-Vinay, Aurelien Marabelle, Rastilav Bahleda, Antoine Hollebecque, Cristina Smolenschi, Anas Gazzah, Jean-Marie Michot, Patricia Martin-Romano, Aurore Vozy, Perrine Vuagnat, François-Xavier Danlos, Arnaud Bayle, Linda Mahjoubi, Barbara Pistilli, Yohann Loriot, Santiago Ponce-Aix, Kaissa Ouali. COBRA: Characteristics and Outcomes of patients with BReast cancer in phAse I trials at Gustave Roussy Cancer center [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-13-02.

Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas’ primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti–PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology. Significance: Sequential explorations of fresh tumor biopsies demonstrated that mesothelioma resistance to anti–PD-1 + antiangiogenics is not due to a lack of tumor T-cell infiltration but rather due to adaptive immunosuppressive pathways by tumors, involving molecules (e.g., IL6, CXCL8, VEGF, and CTLA4) that are amenable to targeted therapies. This article is highlighted in the In This Issue feature, p. 799

Background and ObjectivesD-2-hydroxyglutarate (2HG) characterizesIDH-mutant gliomas and can be detected and quantified with edited MRS (MEGA-PRESS). In this study, we investigated the clinical, radiologic, and molecular parameters affecting 2HG levels.MethodsMEGA-PRESS data were acquired in 71 patients with glioma (24 untreated, 47 treated) on a 3 T system. Eighteen patients were followed during cytotoxic (n = 12) or targeted (n = 6) therapy. 2HG was measured in tumor samples using gas chromatography coupled to mass spectrometry (GCMS).ResultsMEGA-PRESS detected 2HG with a sensitivity of 95% in untreated patients and 62% in treated patients. Sensitivity depended on tumor volume (>27 cm3;p= 0.02), voxel coverage (>75%;p= 0.002), and expansive presentation (defined by equal size of T1and FLAIR abnormalities,p= 0.04). 2HG levels were positively correlated withIDH-mutant allelic fraction (p= 0.03) and total choline levels (p< 0.001) and were higher inIDH2-mutant compared withIDH1R132H-mutant and non–R132HIDH1-mutant patients (p= 0.002). In patients receiving IDH inhibitors, 2HG levels decreased within a few days, demonstrating the on-target effect of the drug, but 2HG level decrease did not predict tumor response. Patients receiving cytotoxic treatments showed a slower decrease in 2HG levels, consistent with tumor response and occurring before any tumor volume change on conventional MRI. At progression, 1p/19q codeleted gliomas, but not the non-codeleted, showed detectable in vivo 2HG levels, pointing out to different modes of progression characterizing these 2 entities.DiscussionMEGA-PRESS edited MRS allows in vivo monitoring of 2-hydroxyglutarate, confirming efficacy ofIDHinhibition and suggests different patterns of tumor progression in astrocytomas compared with oligodendrogliomas.

Although the role of epigenetic alterations in oncogenesis has been well studied, their prevalence in metastatic solid tumours is still poorly described. We therefore aimed at: (i) describing the presence of epigenetic gene alterations (EGA) - defined by an alteration in a gene encoding an epigenetic regulator; and (ii) evaluating their relationship with clinical characteristics and outcome in patients (pts) included in prospective molecular profiling trials.On-purpose tumour biopsies from pts with metastatic solid tumours enrolled in the Gustave Roussy-sponsored MOSCATO (NCT01566019) and MATCHR (NCT02517892) trials were molecularly profiled using whole exome sequencing (WES). Alterations in 176 epigenetic genes were assessed and classified as pathogenic variants (PV) or non-pathogenic variants by a molecular tumour board. Clinical characteristics and outcome were collected.Between Dec 2011 and Oct 2016, WES was successfully performed in 292 pts presenting various solid tumours. We found 496 epigenetic gene alterations in 134 patients (49%), including 237 pathogenic variants in 86 patients; 63 tumour samples (47%) presented ≥3 EGAs. The median number of previous treatment lines was 3 (1-10). The most frequently altered genes were KMT2D and KMT2C (16% each), ARID1A and SETD2 (10% each) and KMT2A (8%).; 31% of EGA co-occurred with a driver gene alteration (p amp;lt; 0.001). Outcome was not correlated with the presence of EGA.Epigenetic alterations occur frequently in metastatic solid tumours. With the current development of epigenetic modifiers, they increasingly represent actionable targets. Such genes should now be systematically analysed in molecular profiling studies.

Immuno-Histo-Chemistry scoring of baseline tumor biopsies according to their DCB status.

Cytotoxic response in tumor biopsies of patients with No DCB upon combination treatment.

Cancer immunotherapy combinations have recently been shown to improve the overall survival of advanced mesotheliomas, especially for patients responding to those treatments. We aimed to characterize the biological correlates of malignant pleural mesotheliomas’ primary resistance to immunotherapy and antiangiogenics by testing the combination of pembrolizumab, an anti–PD-1 antibody, and nintedanib, a pan-antiangiogenic tyrosine kinase inhibitor, in the multicenter PEMBIB trial (NCT02856425). Thirty patients with advanced malignant pleural mesothelioma were treated and explored. Unexpectedly, we found that refractory patients were actively recruiting CD3+CD8+ cytotoxic T cells in their tumors through CXCL9 tumor release upon treatment. However, these patients displayed high levels of somatic copy-number alterations in their tumors that correlated with high blood and tumor levels of IL6 and CXCL8. Those proinflammatory cytokines resulted in higher tumor secretion of VEGF and tumor enrichment in regulatory T cells. Advanced mesothelioma should further benefit from stratified combination therapies adapted to their tumor biology.Significance:Sequential explorations of fresh tumor biopsies demonstrated that mesothelioma resistance to anti–PD-1 + antiangiogenics is not due to a lack of tumor T-cell infiltration but rather due to adaptive immunosuppressive pathways by tumors, involving molecules (e.g., IL6, CXCL8, VEGF, and CTLA4) that are amenable to targeted therapies.This article is highlighted in the In This Issue feature, p. 799

Sup Data Table S1: Characteristic features of long responder patients Sup Data Figure S1: a: PFS and OS from the first objective response assessed for responder patients; b: PFS and OS from the first objective response assessed for partial responders; c: OS and PFS from the first complete response assessed (crPFS and crOS) Sup Data Figure S2: Risk of relapse upon therapy discontinuation function of therapy duration Sup Data Figure S3: Survival from relapse and PFS from OR of secondary refractory disease Sup Data Figure S4: PFS from OR of secondary refractory disease function of tumor type Sup Data Table S2: Characteristics of secondary refractory disease Sup Data Table S3: Characteristics of long survival after immunotherapy initiation with progression first response/stable disease then progression: n=30 (%) Sup Data Table S4: Objective response rate (ORR) as a function of tumor type (%) Sup Data Figure S5a: PFS function of RMH score Sup Data Figure S5b: OS function of the RMH score Sup Data Figure 6: a: Overall survival function of NLR, b: Overall survival for patients presenting progressive disease as best response function of the NLR, c: Overall survival for patients presenting stable disease as best response function of the NLR d: Overall survival for patients presenting objective response as best response function of the NLR Sup Data Figure S7: a: Response function of neutrophil and lymphocyte counts, b: comparison of lymphocyte count function of response, c: comparison of neutrophil count function of response

Purpose:Anti–PD-(L)1 can provide overall survival (OS) benefits over conventional treatments for patients with many different cancer types. However, the long-term outcome of cancer patients responding to these therapies remains unknown. This study is an exploratory study that aimed to describe the long-term survival of patients responding to anti–PD-(L)1 monotherapy across multiple cancer types.Patients and Methods: Data from patients treated with an anti–PD-(L)1 monotherapy in a phase I trial at Gustave Roussy were retrospectively analyzed over a period of 5 years. All cancer types (n = 19) were included. Clinical and biological factors associated with response, long-term survival, and secondary refractory disease were studied.Results:Among 262 eligible patients, the overall objective response rate was 29%. The median progression-free survival of responder patients (RP) at 3 months was 30 months, and the median OS of RP was not reached after a median follow-up of 34 months. In RPs, 3- and 5-year OS percentages were 84% and 64%, respectively. No death occurred in the 21 complete responders (CR) during the overall follow-up. However, many partial responders (PR) showed subsequent tumor relapses to treatment. Long responders (response ≥2 years) represented 11.8% of the overall population. These findings should be validated in further prospective studies.Conclusions:There are currently no differences in therapeutic strategies between CRs and PRs to anti–PD-(L)1. We found a striking difference in OS between these two types of responses. Our results are in favor of evaluating patient stratification strategies and intensification of treatments when tumor lesions of a partial responder to immunotherapy stop improving.See related commentary by Cohen and Flaherty, p. 910

Recent studies showed that patients with glioma can safely participate in early phase clinical trials; however, clinical benefits in this population were limited. We aimed to evaluate the benefit of molecular profiling to guide enrolment in early phase trials for patients with recurrent glioma.Records of patients enrolled in early phase trials of cytotoxic therapies, small molecule inhibitors or monoclonal antibodies from 2008 to 2018 were reviewed for clinico-pathological characteristics, toxicity, response, progression-free survival and overall survival (OS). The primary objective was to evaluate response rates in molecularly-oriented versus non-molecularly-oriented patients.Eighty-eight patients were enrolled, of whom 45 (51.1%) patients were molecularly-oriented. Targets included IDH1/2 (n = 15), BRAF (n = 11), and FGFR1 (n = 3) mutations, FGFR2-3 fusions (n = 9), and mismatch repair deficiency (n = 7). Among patients with high-grade glioma (n = 74), the rate of stable disease ≥6 months and partial or complete response was 25.7% in molecularly-oriented versus 5.1% in non-molecularly-oriented patients (p = 0.02). Upon multivariable adjustment, baseline steroid use ≥20 mg prednisone equivalent per day was associated with shorter OS (OR 3.15 [95% CI 1.62-6.13], p = 0.0008), while molecular enrichment strategy was associated with longer OS (OR 0.40 [95% CI 0.22-0.73], p = 0.003). Nine (10.2%) patients experienced grade 3-4 toxicity and no dose limiting toxicity (DLT) occurred in both cohorts.The use of molecular profiling to guide enrolment in early phase trials is feasible and might provide benefits to selected patients with glioma. Further studies are warranted to confirm these results in larger randomised settings and identify the patients most likely to benefit from this approach.

Sarcoid-like granulomatosis (SLG) reaction caused by immunotherapy remains poorly understood. This study aims to investigate the outcome of patients with cancer and SLG associated with immunotherapy.Between April 2016 and June 2020, 434 patients with immunological adverse events were screened from the ImmunoTOX assessment board of Gustave Roussy, an academic cancer centre in France. Among them, 28 patients had SLG associated with immunotherapy (SLG cohort) and 406 patients had other immunological adverse events (control cohort). Clinical characteristics and outcome of patients were compared from SLG and control cohort.The SLG cohort consisted of 28 patients, 14 women and 14 men, with the median (range) age of 56.5 (28.7-75.3) years. Patients in the SLG cohort with sarcoidosis were asymptomatic (only radiographical finding) in 13 (46.4%) cases; otherwise, the most frequent symptoms were dyspnoea in 8 (28.6%) patients and cough in 5 (17.8%) patients. The computerised tomography scan found sarcoidosis localisations in mediastinal or peri-hilar thoracic lymph nodes in 26 (92.9%) patients, and lung parenchymal involvement was found in 14 (50.0%) patients. The radiographic Scadding stages for sarcoidosis classification were distributed in stages 0, I, II, III and IV in 2 patients (7.1%), 13 patients (46.4%), 11 patients (39.3%), 1 patient (3.6%) and 1 patient (3.6%), respectively. Compared with patients with other immunological toxicities (cohort control), patients with sarcoidosis presented most frequently with melanoma (75.0% versus 21.9% of patients; p 0.001) and more often received combined therapies of anti-programmed cell death 1 plus anti-cytotoxic T-lymphocyte antigen 4 protein (46.4% versus 12.6% of patients; p = 0.002). Patients with sarcoidosis had an improved overall survival (OS); the median OS was not reached in the SLG cohort and 40.4 months in the control cohort, hazard ratio = 0.232 (95% confidence interval: 0.086-0.630) (p = 0.002).Sarcoidosis-like reactions in patients receiving immunotherapy were reported as non-severe immunological reactions in most cases and were correlated with improved OS. SLG should not be misdiagnosed as tumour progression in patients receiving immunotherapy treatment for cancer.

Advances in molecular profiling of newly diagnosed diffuse large cell B lymphoma (DLBCL) have recently refine genetic subgroups. Genetic subgroups remain undetermined at the time of relapse or refractory (RR) disease. This study aims to decipher genetic subgroups and search for prognostic molecular biomarkers in patients with RR-DLBCL. From 2015 to 2021, targeted next-generation sequencing analyses of germline-matched tumor samples and fresh tissue from RR-DLBCL patients were performed. Unsupervised clustering of somatic mutations was performed and correlations with patient outcome were sought. 120 patients with RR-DLBCL were included in LNH-EP1 study and a molecular tumor landscape was successfully analyzed in 87% of patients (104/120 tumor samples). The median age was 67.5 years (range 27.4-87.4), median number of previous treatments was 2 (range 1-9). The most frequently mutated genes were TP53 (n=53 mutations; 42% of samples), CREBBP (n=39; 32%), BCL2 (n=86; 31%), KMT2D (n=39; 28%) and PIM1 (n=54; 22%). Unsupervised clustering separated three genetic subgroups entitled BST (enriched in BCL2, SOCS1 and TNFRSF14 mutations); TKS (enriched in TP53, KMT2D and STAT6 mutations); and PCM (enriched in PIM1, CD79B and MYD88 mutations). Median overall survival was 11.0 (95%CI: 8.1-12.6) months. Overall survival was not significantly different between the three genetic subgroups. GNA13 mutant was significantly associated with an increased risk of death (HR: 6.6 [95%CI: 2.1-20.6]; p=0.0011) and shorter overall survival (p=0.0340). At the time of relapse or refractory disease, three genetic subgroups of DLBCL patients were delineated, which could help advance precision molecular medicine programs. This article is protected by copyright. All rights reserved.

PURPOSE To facilitate implementation of precision medicine in clinical management of cancer, the European Society of Medical Oncology proposed in 2018 a new scale to harmonize and standardize the reporting and interpretation of clinically relevant genomics data (ESMO Scale of Actionability of molecular Targets [ESCAT]). This study aims to characterize the clinical impact of matching targetable genomic alterations (GAs) in patients with advanced cancer according to ESCAT. MATERIAL AND METHODS Analysis of next-generation sequencing results from 552 patients is included in two prospective precision medicine studies at Gustave Roussy. End points included objective response rates, progression-free survival, and overall survival according to ESCAT. RESULTS Molecular data from 516 patients were available and discussed within a Molecular Tumor Board. The most common tumor types were GI (n = 164; 30%), lung (n = 137; 25%), and urologic tumors (n = 68; 13%). Overall, 379 GAs were considered as actionable targets according to ESCAT in 348 (67%) patients. In 31 (6%) patients, two concomitant actionable targets were identified. On the basis of ESCAT, GAs were considered to be classified as tier I in 120 patients (29%), II in 25 patients (5%), III in 80 patients (16%), and IV in 153 patients (30%). A total of 136 patients (27%) received a matched therapy. ESCAT was significantly associated with objective response rates and clinical benefit rates. The median progression-free survival was 6.5 months (95% CI, 4.2 to 8.9), 3 months (95% CI, 1 to not available), 3 months (95% CI, 2.2 to 3.8), and 4 months (95% CI, 2.8 to 6.3) for ESCAT I, II, III, and IV, respectively ( P = .0125). CONCLUSION Implementation of ESCAT classification for clinical decision making by Molecular Tumor Board is feasible and useful to better tailor therapies in patients with cancer.

Immunosenescence is a progressive remodeling of immune functions associated with a decreased ability of the immune system to set up an efficient immune response, both innate and adaptive, with an increase of highly differentiated T cells at the expense of naive T cells. The incidence and prevalence of most cancers increase with age, which can partly be explained by tumor escape mechanisms and decreased immunosurveillance. Aging is also associated with inflammaging, a low-grade proinflammatory state characterized by an increase in inflammatory mediators. Anti-cancer immunotherapy has profoundly changed the landscape of oncology therapy in the last 10 years. Modern T-cell targeted therapies such as bispecific T cell engagers, CAR-T cells, or immune checkpoint blockers may be theoretically affected by immunosenescence or inflammaging.A bibliographic review through PubMed and Embase was carried out using the following search terms: 'immunosenescence,' 'immunotherapy,' 'inflammaging,' 'bispecific antibodies,' 'CAR-T cells,' 'immune checkpoint blockers,' and 'older patients.'This review explores the potential impact of immunosenescence and inflammaging on anti-cancer immunotherapy and therapeutic strategies that could counter immune senescence. A more dedicated research on immunosenescence biomarkers in future clinical trials is warranted for the development of new, more effective and safer therapies.

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.

ObjectiveTo assess whether RAF and MEK inhibitors (RAFi/MEKi) can provide long-term clinical benefit in adult patients with BRAF V600–mutant glial and glioneuronal tumors (GGNTs), we analyzed tumor response and long-term outcome in a retrospective cohort.MethodsWe performed a retrospective search in the institutional databases of 6 neuro-oncology departments for adult patients with recurrent or disseminated BRAF V600–mutant GGNTs treated with RAFi/MEKi.ResultsTwenty-eight adults with recurrent or disseminated BRAF V600–mutant gangliogliomas (n = 9), pleomorphic xanthoastrocytomas (n = 9), and diffuse gliomas (n = 10) were included in the study. At the time that treatment with RAFi/MEKi was started, all tumors displayed radiologic features of high-grade neoplasms. Thirteen patients received RAFi as single agents (vemurafenib [n = 11], dabrafenib [n = 2]), and 15 received combinations of RAFi/MEKi (vemurafenib + cobimetinib [n = 5], dabrafenib + trametinib [n = 10]). Eleven patients achieved a partial or complete response (11 of 28, 39%), with a median reduction of −78% in their tumor burden. Responders experienced a median increase of 10 points in their Karnofsky Performance Status (KPS) score and a median progression-free survival of 18 months, which was longer than achieved with first-line treatment (i.e., 7 months, p = 0.047). Responders had better KPS score (p = 0.018) and tended to be younger (p = 0.061) and to be treated earlier (p = 0.099) compared to nonresponders. Five patients were rechallenged with RAFi/MEKi at progression, with novel tumor responses in 2. On univariate and multivariate analyses, response to RAFi/MEKi was an independent predictor of overall survival.ConclusionsOur study highlights the long-term clinical benefits of RAFi/MEKi in adult patients with BRAF V600–mutant GGNTs and encourages rechallenge in responders.Classification of EvidenceThis study provides Class III evidence that, for adult patients with BRAF V600-mutant GGNT, RAFi/MEKi can reduce tumor burden and provide clinical benefit.

Resume La population des sujets âges represente pres de 60 % des nouveaux diagnostics de cancer. Leur prise en charge, le plus souvent complexe, est un probleme de sante publique. L’heterogeneite du vieillissement rend indispensable une evaluation de l’etat global, notamment pour eviter le sur-traitement (ou sous-traitement), et pouvoir reperer les patients âges fragiles ou vulnerables qui risquent d’avoir plus de toxicites des traitements. A travers cet article, nous rappellerons l’importance de l’evaluation geriatrique approfondie (EGA) en detaillant les differents facteurs qui impactent la decision therapeutique, la tolerance aux traitements… Cette EGA est cependant chronophage et tous les patients ne peuvent etre evalues. Afin d’identifier les sujets relevant de cette EGA, des echelles de screening ont ete developpees. Nous developperons enfin la place de la recherche dans la prise en charge oncogeriatrique.

BACKGROUND Patients with recurrent glioma have limited treatment options. The anti‒ PD-1 monoclonal antibody pembrolizumab demonstrated antitumor activity as monotherapy in a subset of patients with PD-L1–positive recurrent glioblastoma (GBM) in the KEYNOTE-028 study; and durable clinical benefit in patients with previously treated unresectable/metastatic MSI-H/dMMR non-colorectal tumors in the multicohort KEYNOTE-158 (NCT02628067) study. We report outcomes with pembrolizumab in patients with MSI-H/dMMR recurrent glioma enrolled in KEYNOTE-158. METHODS Adults with MSI-H/dMMR recurrent glioma, measurable disease per RECIST v1.1, ECOG PS 0/1, and tumor sample for biomarker analysis were eligible for cohort K (any MSI-H/dMMR advanced solid tumor, except colorectal cancer; local, prospective determination of MSI-H/dMMR status by PCR and/or IHC). Patients received pembrolizumab 200 mg Q3W for up to 35 cycles or until PD/unacceptable AEs (clinically stable patients could continue treatment until PD confirmed after ≥ 4 weeks). Primary endpoint was ORR per RECIST v1.1 by independent central review. RESULTS Among 21 enrolled patients, all received prior temozolomide, 12 (57%) received prior bevacizumab, and 14 (67%) received ≥ 2 prior lines of therapy. 14 (67%) patients had GBM, 4 (19%) had oligodendroglioma/oligoastrocytoma, and 3 (14%) had glioma NOS. Median time from first dose to data cutoff (January 12, 2022): 50.0 months; 19 (90%) patients discontinued treatment. 1 patient with GBM had PR (ORR, 4.8% [95%CI, 0.1%‒23.8%]); duration of response was 18.9 months, PFS 29.2 months, and OS 32.7 months. 3 (14%) patients had SD; PFS was 23.2, 14.5, and 3.3 months; OS was 23.2, 15.1, and 9.1 months. Overall, median PFS and OS (95%CI) were 1.4 (1.0‒2.1) months and 5.6 (2.6‒16.2) months. Treatment-related AEs occurred in 7 (33%) patients (grade 3/4, n = 1; no grade 5) and led to discontinuation in 1 (5%) patient. CONCLUSIONS Pembrolizumab demonstrated antitumor activity with manageable toxicity in a small subset of patients with relapsing/refractory MSI-H/dMMR glioma.

Background: About 40% of breast cancer cases occur in women 65 years old (yo) or older and 20% in women over 75 yo. These numbers are expected to increase in the near future. Ironically, older patients remain underrepresented in clinical trials with no improvement in the past decade, although they may present different efficacy/toxicity profiles compared with younger adults. In this context, real life cohorts may bring valuable insight to identify potential barriers to recruitment of older patients with metastatic breast cancer (MBC) in clinical trials. Methods: We used the national Epidemio-Strategy and Medical Economics (ESME) MBC Data Platform, a multi-center real life database using a retrospective data collection process in 18 French Cancer Centers. Cases selected were adult patients with MBC whose first metastasis was treated between January 1st, 2008 and December 31st, 2016. We selected MBC women over 70 yo at the time of MBC diagnosis, with at least one line of systemic treatment and no other cancer in the 5 years before MBC. The primary objective was to describe factors associated with enrollment in clinical trials in older patients, using a multivariable Cox model. Factors included in this model were age (continuous, and by class), period (2008-2011 vs 2012-2016), phenotype (ER+, HER2+, or ER- HER2-), ECOG Performance Status (PS), treatment, metastatic sites (brain, visceral, nodes/bone only) and number, and volume of hospital activity. No geriatric description could be extracted from the database. Results: There were 5846 patients ≥70yo (median age 77) and 15892 patients < 70 yo. Of the older ones, 245 (4.2%) were enrolled in a clinical trial in first line compared with 1602 (10%) for younger ones. Most of the older patients in this cohort (66%) had ER+ HER2+ disease, half had visceral metastases (< 3 metastatic sites in 82%). Median follow-up of older patients was 46.3 months; 95%CI 44.8-49.0. Cause of death was related to disease in 1155 (33.9%) older patients, and related to another cause or unknown in 2156 (63.3%), data were missing for 2441 patients. Median overall survival (OS) was 34.1 months in the older population, 95%CI 32.9-35.4, and specific overall survival was 70.8 months, 95%CI 66.3-80.0. Significant factors identified in the multivariable analysis for enrollment in 1st line treatment clinical trial ≥70 are shown in table. Volume of activity was not identified as one. By multivariate analysis, participation of older patients to a clinical trial was associated with an increased OS (HR 0.7; 95% CI 0.6-0.8) but not with a better breast cancer specific survival (HR 0.94; 95%CI 0.68-1.29). Conclusions: In this large real-life database, few older MBC patients were enrolled in a trial compared with younger ones. Factors associated with such participation to clinical research were younger age (< 80 yo), good PS, HER2+ disease, and investigational treatment consisting of chemotherapy or targeted therapy. There was a small improvement in accruing older patients between 2007-2011 and 2012-2016 (2.6% versus 5.5%). Most of these factors raise questions on drug availability and perceived potential benefits by investigators and medical teams. Accrual of older patients with cancer in other disease types should be more encouraged. VariableOR95%CIAge vs 70-75 75-80 80-85 85+0.74 0.47 0.170.54-1 0.31-0.71 0.06-0.37MBC diagnosis period vs 2008-2011 2012-20161.671.23-2.27Phenotype vs Others HER2+1.761.26-2.45PS vs 0 1 2-40.71 0.150.5-1 0.08-0.26Treatment4.88 5.253.08-7.9 3.48-8.14Chemotherapy vs others4.883.08-7.9Targeted treatment vs others5.253.48-8.14 Citation Format: Michael Bringuier, Matthieu Carton, Christelle Levy, Anne Patsouris, David Pasquier, Marc Debled, Olivier Rigal, William Jacot, Anthony Gonçalves, Isabelle Desmoulins, Thibault De La Motte Rouge, Thomas Bachelot, Jean-Marc Ferrero, Jean-Christophe Eymard, Florence Dalenc, Marie-Ange Mouret-Reynier, Thierry Petit, Michael Chevrot, Coralie Courtinard, Lionel Uwer, Jean-Sebastien Frenel, Capucine Baldini. Enrollment of older metastatic breast cancer patients in clinical trials [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-46.

221 Background: AR ligand binding domain (LBD) activating somatic point mutation is a known mechanism of resistance to androgen-receptor signaling inhibitor (ARSI) treatment in mCRPC, leading to a persistent addiction to steroid hormones. Two early phase trials investigating CYP11A1 inhibitors - CYPIDES (ODM208, NCT03436485) and STESIDES (ODM209, NCT03878823) - recruited mCRPC patients with and without pre-specified AR LBD mutation. In CYPIDES Part 1, AR LBD mutations (ARm) strongly predicted for PSA decline with ODM-208 (Fizazi, ASCO GU 2021). Here, we evaluated clinical and genomic data associated with ARm in patients with mCRPC. Methods: We reviewed clinical and molecular data from patients with mCRPC who progressed after ≥1 ARSI and ≥1 line of taxane-based chemotherapy or were ineligible to chemotherapy, pre-screened in CYPIDES and STESIDES trials at our center. Circulating tumor DNA (ctDNA) was tested for AR LBD mutation (Guardant360 CDx and Sysmex OncoBEAM) and for genomic analysis (FoundationOne Liquid CDx, STING trial, NCT04932525) to screen for actionable targets. Results: From March 2020 to January 2022, 272 men were screened. Median age was 62y. Overall, 212 (78%), 202 (74%), and 240 (88%) patients had received previous abiraterone, enzalutamide, and docetaxel respectively. Median PSA at screening was 59 ng/mL (IQR 11; 246). ARm was found in 69 patients (25%). The most frequent mutations were L702H (15%), T878A (12%), H875Y (7%), V716M (2%), F877L (2%), W742C (1%), globally consistent with previous reports. Associations of ARm with relevant baseline characteristics of patients are summarized. Duration of enzalutamide exposure was correlated with the number of AR mutations per patient (p = 0.006) whereas no correlation was found for abiraterone exposure duration (p=0.71). In 173 (64%) patients with available genomic testing, no alterations were found to be mutually exclusive with ARm, including in DNA repair alteration. Conclusions: AR LBD mutations were detected in ctDNA in 25% of men with advanced mCRPC treated with at least one ARSI. Their incidence was associated with a longer duration of treatment with enzalutamide and a longer time from CRPC and prostate cancer diagnosis. [Table: see text]

498 Background: BT8009 is a Bicycle Toxin Conjugate (BTC), a novel class of chemically synthesized molecules comprising a small (~2 kDa) bicyclic peptide targeting Nectin-4 tumor antigen linked to cytotoxin MMAE via a valine-citrulline cleavable linker. BTCs represent a unique therapeutic class, distinct from ADCs and with pharmacokinetic properties analogous to small molecules. Presented are the monotherapy dose escalation results of the ongoing Phase I/II clinical trial of BT8009 (NCT04561362). Methods: In the Part A 3+3 dose escalation portion of the study, BT8009 monotherapy was administered weekly (2.5, 5, 7.5 mg/m2) or every other week (7.5, 10 mg/m2) of a 28-day cycle, or on days 1 and 8 of a 21-day cycle (7.5 mg/m2). Primary objectives were to assess safety of the monotherapy and define maximum tolerated and recommended Phase II dose(s) (RP2D). Key secondary objectives were antitumor activity per RECIST v1.1 and PK parameters. Results: At time of the 20 Sept 2022 data cut-off, 49 pts had received BT8009 (24 pts with UC): weekly (7 pts at 2.5 mg/m2, 20 pts at 5 mg/m2, 5 pts at 7.5 mg/m2); biweekly (5 pts at 7.5 mg/m2, 7 pts at 10 mg/m2); and days 1+8 of a 21-day cycle (5 pts at 7.5 mg/m2). Two RP2Ds have been determined: 5 mg/m2 given weekly on a 28-day cycle and 7.5 mg/m2 given on days 1+8 of a 21-day cycle. Median age was 66 y, 59% pts were male, and median prior lines of therapy was 3 (range 1-15). Most common treatment-related adverse events of any grade experienced by ≥15% of pts were nausea, fatigue, diarrhea, decreased appetite, alopecia, asthenia, pyrexia, and neutrophil count decreased/neutropenia; majority were mild to moderate in severity. One DLT (G3 asthenia) was reported at the 7.5 mg/m2 weekly dose level and 1 DLT (G4 sepsis) at the 10 mg/m2 biweekly dose level. Treatment-related SAEs occurred in 5 pts. No pt discontinued treatment due to an AE. No treatment-related deaths occurred. Of 8 efficacy evaluable pts with UC treated with a RP2D of 5 mg/m2, there was 1 complete response, 3 partial responses (PR), and 3 stable diseases (SD), for an ORR of 50% and clinical benefit rate of 75% (CR+PR+SD≥16 wks). Median duration of response has not yet been reached, but as of 20 Sept 2022 was at least 11 months. Both plasma BT8009 and MMAE exhibited linear pharmacokinetics, with short half-life for BT8009 (

Introduction: Immunotherapy is one of the mainstays of lung cancer treatment. The results presented in pivotal trials do not always reflect real life, since patients (pts) are more selected for prognostic factors. Cancer is associated with advanced age and aging is the main risk factor for developing CHIP, which refers to the finding of one or more mutations affecting genes involved in hematologic malignancies in pts without hematologic disease per se. Objective: To evaluate CHIP prevalence in a prospective cohort of 104 pts treated with ICB for NSCLC and to correlate CHIP and clinical outcomes. Materials and methods: We performed a Next-Generation Sequencing (NGS) with a panel of 74-genes dedicated to hematological alteration on DNA extracted from whole blood collected before the first administration of an ICB, within the PREMIS trial (NCT03984318). To estimate the prevalence of CHIP, we selected the following 4 CHIP genes; DNMT3A, TET2, ASXL1 and JAK2. CHIP prevalence was assessed according to two variant allele frequency (VAF) thresholds (1% and 2%). The results were analyzed for the entire population and for the subgroup of pts older than 70 years. Results: We included 104 pts; 68 pts (65%) male, median age of 68 years [range 31-87] and adenocarcinoma represented the 68%. PD-L1 50%: 43%. ICB setting was 1°L 41%; 2°L 47%; > 3°L 11%, and the most used ICB was Pembrolizumab in 63% of pts. Among the 88% of the pts who discontinued treatment, 63% did it due to disease progression and 13% due to toxicity (pneumonitis was the most frequent adverse event in pts with CHIP). Overall, at least 1 CHIP mutation was found in 35 pts (34%). Incidence at VAF 1% and 2% for each mutation were DNMT3A 80% and 69%, TET2 11% respectively, ASXL1 11% respectively and JAK2 6% and 3%; for older pts subgroup VAF at 1% and 2% were: DNMT3A 71% and 59% and for TET2 and ASXL1 24% respectively for each mutation. Only 4% of pts had more than 1 CHIP mutation. No pts developed hematological disease during the follow up. There was no difference in CHIP prevalence according to line of treatment. CHIP pts achieved disease control in 51%. PFS and OS results will be presented at the conference. Conclusion: CHIP is commonly found in pts with solid tumors, including NSCLC, with a prevalence in our cohort of 34%, which is lower than that reported in literature. No pts developed a characterized hematological disease during follow up. Survival outcomes will be presented at the conference. Citation Format: Julieta Elena Rodriguez, Capucine Baldini, Francois Xavier Danlos, Aurelien Marabelle, Maxime Frelaut, Marco Tagliamento, Mihaela Aldea, Benjamin Besse, Jean Baptiste Micol, Christophe Marzac, Nathalie Chaput, Christophe Massard. Clonal hematopoiesis of indeterminate potential (CHIP) in patients with advanced NSCLC treated with immune checkpoint blockers (ICB) as monotherapy: Analysis of the PREMIS study. [R] [abstract]. In: Proceedings of the AACR Special Conference: Aging and Cancer; 2022 Nov 17-20; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2022;83(2 Suppl_1):Abstract nr A027.

Patients enrolled in oncology phase 1 trials (ph1) usually have advanced heavily pre-treated cancers with few therapeutic options. Quality of life (QoL) is one of the key cancer-treatment outcome measures, especially in ph1, and sexuality is an important part of Qol but rarely explored. This prospective study aims to assess supportive care needs, QoL and sexuality in ph1.Between September 2020 and June 2021, we prospectively recruited patients enrolled in ph1 at Gustave Roussy in France. Supportive care needs, QoL (EORTC QLQ-C30) and sexuality (female sexual function index for women, male sexual health questionnaire [MSHQ] for men) were assessed at baseline, one, three and 5 months. We performed multivariate analyses to identify associations between clinical characteristics, QoL and quality of sexual life over time.At baseline, we analyzed 187 patients (45% women (n = 84) and 55% men (n = 103)). Patients expressed the need for consultations in pain management, nutrition, psychology and sexology in 28%, 26%, 19% and 9%, respectively. Lower global QoL was independently associated with Royal Marsden Hospital score (p = 0.012), urogenital location tumor (p = 0.021), elevated CRP levels (p = 0.014) and pain intensity (p = 0.005). Ninety-two percent of women had sexual dysfunction. In men, a lower MSHQ score was independently associated with urogenital location tumor (p = 0.021), ECOG Performance Status (p = 0.006), comorbidity at risk (p = 0.024) and pain intensity (p = 0.004).There are significant needs for supportive care in ph1, especially in some subgroups of patients. New models of care should be developed to improve early phase pathways.

Immune checkpoint blockers (ICBs) have a pivotal role in the management of non-small cell lung cancer (NSCLC), both as single agent and in combination strategies, providing a meaningful clinical and survival benefit. Older patients are underrepresented in clinical trials, including those involving immunotherapy, even though almost half of the patients with newly diagnosed NSCLC are aged 70 years or older. Moreover, due to selection biases, usually "fit" patients are preferably enrolled. This results in a lack of evidence regarding the use of ICBs in the older population, particularly when referring to chemo-immunotherapy regimens. Since ICBs are indeed of paramount importance in the treatment of patients with NSCLC, efforts are needed to optimize their use also in the older population. This entails furthermore taking into account additional features including the degree of fitness of the patient and the different health domains that can be affected by aging. This review aims to delve into the current evidences about the efficacy and toxicity of ICBs in monotherapy and in combination in older patients with advanced NSCLC, the role of the comprehensive geriatric assessment in supporting the selection of patients receiving immunotherapy, as well as the value of immunosenescence in modulating the activity of these drugs.

Many intratumoural (IT) immunotherapies are currently developed in the clinic with the aim of overcoming primary and secondary resistance and/or to limit on-target/off-tumour toxicities of immune checkpoint targeted therapies. This study aimed to describe the feasibility, safety and efficacy of IT immunotherapy treatments.This retrospective single-centre study included the first 100 consecutive patients enrolled in Gustave Roussy's Human IntraTumoral-ImmunoTherapy (HIT-IT) program. Patient characteristics, target description, image guidance, safety and response according to iRECIST (Response Evaluation Criteria in Solid Tumours for immunotherapy trials) were recorded. Predictive factors of complications and responses were analysed. Survival was also reported.From 09/2015 to 05/2020, 100 patients had 115 tumours injected during 423 treatment cycles. Most frequent primary tumour arose from the skin (n = 49), digestive track (n = 4) or head and neck (n = 8). Injected tumours' mean diameter was 37 ± 23 mm, and a median number of 4 IT injections per patient (interquartile range:3-5) were performed. Targeted tumours for IT injections were superficial lymph nodes (36.5%), subcutaneous lesions (25.2%), liver tumours (20.9%) and others (17.4% including tumour sites such as deep lymph nodes or lung). Most patients (72%) received systemic immunotherapy in combination with HIT-IT. Procedure- and drug-related adverse events (AEs) occurred in 11.3% and 33.3% of the treatment cycles, respectively. Only 3 procedure-related AEs were grade-3 (0.7%); and no grade-4 or 5 occurred. Among all cycles, 7 grade-3 and 1 grade-5 drug-related AEs were reported. Complete and partial responses were achieved for 5% and 18% of patients, respectively, while stable disease was the best response for 11%. Patients receiving HIT-IT as a 1st-line treatment (24%), or not previously pre-treated with immunotherapy (53%) responded better, p = 0.001 and p = 0.004, respectively. From 1st cycle of IT, 12-month overall progression-free survival and overall survival were 21% (14-31%) and 57% (47-68%), respectively.This retrospective study, conducted on patients with cancer and treated within clinical trials at Gustave Roussy, demonstrates the feasibility and safety of the IT immunotherapy strategy.

Background Early phase clinical trials usually include patients with advanced disease who have failed standard therapies. Early palliative care for these patients has shown to improve quality of life and even survival. PALLIA 10 score (ranging from 1 to 10) is a tool developed by the French Palliative Care Society to identify the best time to introduce palliative care. Methods We assessed the PALLIA 10 score and other prognostic factors (age, ECOG, Royal Marsden Hospital (RMH) score, LDH and albumin levels, number of prior systemic treatments and metastatic sites) in patients enrolled in phase I trials at Gustave Roussy Cancer Center prospectively during 2 periods of time (cohort 1 (C1) and 2 (C2)). A double-blind assessment of the PALLIA 10 score was done during 15 days by a member of the palliative care unit in C2. A PALLIA 10 > 3 motivated a dedicated palliative care consultation. Results From July 1st 2018 to November 1st 2018 (C1) and from December 1st 2020 to April 16th 2021 (C2), a total of 86 patients were assessed in C1 and 302 in C2. No difference was observed between the two cohorts regarding prognostic factors. Median PALLIA 10 was also similar and very low (median 1, range 1-5 in C1 and 1-8 in C2). On C1 and C2, 12% and 5% of patients had a dedicated palliative consultation. Overall, 77% and 74% of patients in C1 and C2 were still alive beyond 3 months after discontinuation of the trial (p=0.78), followed by at least one subsequent treatment in 63% and 70% of pts. In C2, assessment of PALLIA 10 score was significantly different between palliative care physician (median 5, range 3-8), phase I physician (median 1, range 1 -6) and phase I nurse (median 3, range 1-8) (p

Purpose: Although the role of epigenetic alterations in oncogenesis has been well studied, their prevalence in metastatic solid tumors is still poorly described. We therefore aimed at: (i) describing the presence of epigenetic gene alterations (EGA) - defined by an alteration in a gene encoding an epigenetic regulator; and (ii) evaluating their relationship with clinical characteristics and outcome in patients (pts) included in prospective molecular profiling trials.Patients and methods: On-purpose tumor biopsies from pts with metastatic solid tumors enrolled in the Gustave Roussy-sponsored MOSCATO (NCT01566019) and MATCHR (NCT02517892) trials were molecularly profiled using Whole Exome Sequencing (WES). Alterations in 176 epigenetic genes were assessed and classified as pathogenic variants (PV) or non-pathogenic variants by a molecular tumor board. Clinical characteristics and outcome were collected.Results: Between Dec 2011 and Oct 2016, WES was successfully performed in 292 pts presenting various solid tumors. We found 496 epigenetic gene alterations in 134 patients (49%), including 237 pathogenic variants in 86 patients; 63 tumor samples (47%) presented ≥3 EGAs. The median number of previous treatment lines was 3 (1 – 10). The most frequently altered genes were KMT2D and KMT2C (16% each), ARID1A and SETD2 (10% each) and KMT2A (8%).; 31% of EGA co-occurred with a driver gene alteration (p < 0.001). Outcome was not correlated with the presence of EGA.Conclusions: Epigenetic alterations occur frequently in metastatic solid tumors. With the current development of epigenetic modifiers, they increasingly represent actionable targets. Such genes should now be systematically analyzed in molecular profiling studies.