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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.

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.

Aging is an important risk factor for cancers and is associated with poor prognosis. Weakness of the immune system, also called immunosenescence may occur with older age. The impact of aging on efficacy and safety of immune checkpoint blockers, such as anti-programmed death (ligand) PD-(L)1, remains undetermined. This study aims to evaluate the incidence of immune-related adverse events (irAEs) in patients aged 70 years or older than their younger counterparts.Patients with advanced solid tumors treated at Gustave Roussy with an anti-PD-(L)1 monotherapy between June 2014 and October 2017 were prospectively included within the dedicated irAEs pharmacovigilance registry REISAMIC (Registre des Effets Indésirables Sévères des Anticorps Monoclonaux Immunomodulateurs en Cancérologie). The incidence of irAEs of grade ≥II was compared between patients aged ≥70 (old patients, OP) versus patients aged 70 years (young patients, YP) using a chi-squared test. Survivals were estimated using the Kaplan-Meier method.Among the 603 patients treated by anti-PD(L)1, 191 were ≥70 y.o (OP) and 424 70 y.o (YP). The median (range) age of OP and YP were respectively 77 (70-93) and 59 years old (17-69). A total of 165 irAEs occurred in these patients (103 grade II and 58 grade III-IV). The overall incidence of grade ≥II irAEs was higher in OP than in YP (33% versus 25%, p = 0.03). In addition, OP were more prone of having multiples irAEs compared with YP (p = 0.037). Skin toxicities were more frequent in OP than in YP (p = 0.007) but endocrine toxicities were less frequent in OP than in YP (p = 0.044). This higher level of irAEs seems to be responsible for a higher rate of treatment discontinuation in OP (p = 0.2). There was no statistical difference in median time to toxicity, exposure to steroids or survival between the two groups.Although anti-PD-(L)1 immunotherapies remain an acceptable treatment option for older patients, prescribers should be aware that irAEs are more frequent in the elderly. Further translational studies are warranted to better understand the relationship between aging and irAEs.

Purpose Enrolment process influences the likelihood of patients' inclusion in early clinical trials (ECT) through social, medical and organisational factors. Patients and Methods All patients referred from 2008 to 2016 to the Drug Development Department (DITEP) of Gustave Roussy (GR) were reviewed. Referring physician, organisational factors, medical and socioeconomic characteristics for patients were analysed. Multivariate analysis was performed with regard to those factors. A telephone survey was conducted on a sample of referring physicians located outside GR (N = 142). Results Between 2008 and 2016, 8694 requests were received with 49% from external physicians. Here, 4517 were male patients with a median age of 58 [49–66] years (range 18–85). Tumour types were gastrointestinal (28%), lung (19%), breast (9%) and gynaecologic (8%). Mean enrolment rate was 37% (ranging from 24 to 45%). From 2008 to 2016, the enrolment rate decreases from 39% to 24%. In the meantime, DITEP trials portfolio evolves with the part of precision medicine trials increase from 12% to 40%. Factors that were significantly associated with a lower likelihood of being enrolled were referral from an external physician (OR 0.15 s.16–0.21]) compared to a physician from DITEP and year of the request (2.74 [1.8–2.9] 2008 versus 2016). The enrolment rate and the number of patients addressed have a high variability regarding referring physicians, which is little explained by characteristics as training, previous experience or attitude regarding ECT. Conclusion Beyond patients' individual characteristics, we show that organisational and professional factors have a major impact on likelihood of enrolment in ECT.

INTRODUCTION: A number of phase I immunotherapy trials for cancer patients incorporate the absolute lymphocyte count (ALC) as an inclusion criteria. This study aims to assess whether ALC is associated with a lack of response to anti-PD-1/PD-L1 in early clinical trials. METHODS: All consecutive patients treated with anti-PD-1/PD-L1 monotherapy in phase I trials in our institution between December 2011 and January 2014 were reviewed. Baseline ALC, neutrophil-to-lymphocyte ratio (NLR), Royal-Marsden Hospital (RMH) prognostic score, objective response rate (ORR) and disease control rate (DCR = SD + PR + CR, stable disease (SD), partial response (PR), complete response (CR)) defined by Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 were retrieved. RESULTS: Out of a total of 167 patients, 48 (28.7%) and 8 patients (4.8%) had baseline ALCs of 1 G/l. When using 0.5 G/l as ALC threshold, we did not find any difference either in ORR or in DCR. In a multivariate Cox regression analysis, baseline ALC was not associated with overall survival, whereas the RMH and the number of previous lines of treatment remained independent prognostic factors. CONCLUSIONS: Baseline ALC was not associated with response to anti-PD-1/PD-L1 in cancer patients enrolled in phase I trials. Patients should not be excluded from early phase clinical trials testing immune checkpoints blockers because of ALC.